Aromatic sulfone hydroxamic acid metalloprotease inhibitor

ABSTRACT

A treatment process is disclosed that comprises administering an effective amount of an aromatic sulfone hydroxamic acid that exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibition at least of MMP-1 to a host having a condition associated with pathological matrix metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula (I), below, or a pharmaceutically acceptable salt thereof, wherein R 1  and R 2  are both hydrido or R 1  and R 2  together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two, or three heteroatoms in the ring that are oxygen, sulfur, or nitrogen. R 3  in formula (I) is an optionally substituted aryl or optionally substituted heteroaryl radical. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent is a divisional of U.S. patent application Ser. No.09/554,082 (filed Jul. 31, 2000), now U.S. Pat. No. 6,541,489 which, inturn, claims priority to PCT application PCT/US98/23242 (filed Nov. 12,1998, and published as International Publication No. WO 99/25687),which, in turn, claims priority to U.S. Provisional Patent ApplicationSerial No. 60/066,007 (filed Nov. 14, 1997). This patent also claimspriority to U.S. Provisional Patent Application Serial No. 60/066,007.The entire text of each of the above patent applications is incorporatedby reference into this application.

TECHNICAL FIELD

This invention is directed to proteinase (protease) inhibitors, and moreparticularly to the use of aromatic sulfone hydroxamic acid compoundsthat, inter alia, are selective inhibitors of matrix metalloproteinasesin a process for treating conditions associated with pathological matrixmetalloproteinase activity, the selective inhibitors themselves,compositions of proteinase inhibitors, intermediates for the synthesesof proteinase inhibitors, and processes for the preparation ofproteinase inhibitors.

BACKGROUND OF THE INVENTION

Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals makeup, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason leads to a number of disease states. Inhibition ofthe enzymes responsible loss of equilibrium provides a control mechanismfor this tissue decomposition and, therefore, a treatment for thesediseases.

Degradation of connective tissue or connective tissue components iscarried out by the action of proteinase enzymes released from residenttissue cells and/or invading inflammatory or tumor cells. A major classof enzymes involved in this function are the zinc metalloproteinases(metalloproteases).

The metalloprotease enzymes are divided into classes with some membershaving several different names in common use. Examples are: collagenaseI (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8,neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13),stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions. Examples include rheumatoidarthritis, osteoarthritis, septic arthritis; corneal, epidermal orgastric ulceration; tumor metastasis, invasion or angiogenesis;periodontal disease; proteinuria; Alzheimers Disease; coronarythrombosis and bone disease. Defective injury repair processes alsooccur. This can produce improper wound healing leading to weak repairs,adhesions and scarring. These latter defects can lead to disfigurementand/or permanent disabilities as with post-surgical adhesions.

Metalloproteases are also involved in the biosynthesis of tumor necrosisfactor (TNF), and inhibition of the production or action of TNF andrelated compounds is an important clinical disease treatment mechanism.TNF-α, for example, is a cytokine that at present is thought to beproduced initially as a 28 kD cell-associated molecule. It is releasedas an active, 17 kD form that can mediate a large number of deleteriouseffects in vitro and in vivo. For example, TNF can cause and/orcontribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal, and TNF can helpcontrol the growth of tumor cells.

TNF-α convertase is a metalloprotease involved in the formation ofsoluble TNF-α. Inhibition of TNF-α convertase (TACE) inhibits productionof active TNF-α. Compounds that inhibit both MMPs activity and TNF-αproduction have been disclosed in WIPO International Publication Nos. WO94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs suchas collagenase, stromelysin and gelatinase have been shown to inhibitthe release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehanet al., Nature 376, 558-561 (1994)). There remains a need for effectiveMMP inhibitors. There also remains a need for effective TNF-α convertaseinhibiting agents.

MMPs are involved in other biochemical processes in mammals as well.Included is the control of ovulation, post-partum uterine involution,possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) tothe amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI).Inhibition of these metalloproteases permits the control of fertilityand the treatment or prevention of Alzheimers Disease. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor drug or biochemical such as α₁-PI supports thetreatment and prevention of diseases such as emphysema, pulmonarydiseases, inflammatory diseases and diseases of aging such as loss ofskin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances.Treatment of cancer and/or inhibition of metastasis and/or inhibition ofangiogenesis are examples of approaches to the treatment of diseaseswherein the selective inhibition of stromelysin, gelatinase A or B, orcollagenase III appear to be the relatively most important enzyme orenzymes to inhibit especially when compared with collagenase I (MMP-1).A drug that does not inhibit collagenase I can have a superiortherapeutic profile. Osteoarthritis, another prevalent disease whereinit is believed that cartilage degradation of inflamed joints is at leastpartially caused by MMP-13 released from cells such as stimulatedchrondrocytes, may be best treated by administration of drugs one ofwhose modes of action is inhibition of MMP-13. See, for example,Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al.,J. Clin. Invest., 21:2011-2019 (1996).

Inhibitors of metalloproteases are known. Examples include naturalbiochemicals such as tissue inhibitors of metalloproteinases (TIMPs),α₂-macroglobulin and their analogs or derivatives. These endogenousinhibitors are high molecular weight protein molecules that forminactive complexes with metalloproteases. A number of smallerpeptide-like compounds that inhibit metalloproteases have beendescribed. Mercaptoamide peptidyl derivatives have shown ACE inhibitionin vitro and in vivo. Angiotensin converting enzyme (ACE) aids in theproduction of angiotensin II, a potent pressor substance in mammals andinhibition of this enzyme leads to the lowering of blood pressure.

Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are known as is shown in, for example, WO95/12389,WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMPinhibitors are disclosed in a number of published patent applicationssuch as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 thatdisclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidylback-bones or peptidomimetic back-bones, as does the article by Schwartzet al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen etal., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. NewDrugs, 15(3): 175-185 (1997).

One possible problem associated with known MMP inhibitors is that suchcompounds often exhibit the same or similar inhibitory effects againsteach of the MMP enzymes. For example, the peptidomimetic hydroxamateknown as batimastat is reported to exhibit IC₅₀ values of about 1 toabout 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, andMMP-9. Marimastat, another peptidomimetic hydroxamate was reported to beanother broad-spectrum MMP inhibitor with an enzyme inhibitory spectrumvery similar to batimastat, except that marimastat exhibited an IC₅₀value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).

Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate) indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although marimastat exhibitedsome measure of efficacy via these markers, toxic side effects werenoted. The most common drug-related toxicity of marimastat in thoseclinical trials was musculoskeletal pain and stiffness, often commencingin the small joints in the hands, spreading to the arms and shoulder. Ashort dosing holiday of 1-3 weeks followed by dosage reduction permitstreatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75(1997). It is thought that the lack of specificity of inhibitory effectamong the MMPs may be the cause of that effect.

International application WO 98/38163, published on Sep. 3, 1998disclose a large group of hydroxamate inhibitors of MMPs and TACE. Thecompounds of WO 98/38163 contain one or two substituents adjacent to thehydroxamate functionality and a substituent that can be an aromaticsulfonyl group adjacent to those one or two substituents.

International application WO 98/37877, published on Sep. 3, 1998discloses compounds that contain a 5- to 7-membered heterocyclic ringadjacent to the hydroxamate functionality and can contain an aromaticsulfonyl group adjacent to the heterocyclic ring.

Although many of the known MMP inhibitors such as batimastat, marimastatand the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broadspectrum of activity against MMPs, those compounds are not particularlyselective in their inhibitory activity. This lack of selectivity may bethe cause of the musculoskeletal pain and stiffness observed with theiruse. In addition, it can be therapeutically advantageous to utilize amedicament that is selective in its activity as compared to a generallyactive material so that treatment can be more closely tailored to thepathological condition presented by the host mammal. The disclosure thatfollows describes a process for treating a host mammal having acondition associated with pathological matrix metalloprotease activitythat utilizes a compound that selectively inhibits one or more MMPs,while exhibiting less activity against at least MMP-1.

SUMMARY OF THE INVENTION

The present invention is directed to a treatment process that comprisesadministering a contemplated aromatic sulfone hydroxamic acidmetalloprotease inhibitor in an effective amount to a host mammal havinga condition associated with pathological metalloprotease activity. Acontemplated molecule, inter alia, exhibits excellent inhibitoryactivity of one or more matrix metalloprotease (MMP) enzymes, such asMMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibitionat least of MMP-1. By “substantially less” it is meant that acontemplated compound exhibits an IC₅₀ value ratio against one or moreof MMP-2, MMP-9 or MMP-13 as compared to its IC₅₀ value against MMP-1,e.g., IC₅₀ MMP-2:IC₅₀ MMP-1, that is less than about 1:10, preferablyless than about 1:100, and most preferably less than about 1:1000 in thein vitro inhibition assay utilized hereinafter. The invention alsocontemplates particular compounds that selectively inhibit the activityof one or more of MMP-2, MMP-9 and MMP-13, while exhibitingsubstantially less inhibition at least of MMP-1, as well as acomposition containing such a MMP inhibitor as active ingredient. Theinvention further contemplates intermediates in the preparation of acontemplated aromatic sulfone hydroxamic acid molecule and a process forpreparing an aromatic sulfone hydroxamic acid molecule.

Briefly, one embodiment of the present invention is directed to atreatment process that comprises administering a contemplated aromaticsulfone hydroxamic acid metalloprotease inhibitor that selectivelyinhibits matrix metalloprotease activity as above in an effective amountto a host mammal having a condition associated with pathologicalmetalloprotease activity. The administered enzyme inhibitor correspondsin structure to formula (I), below, or a pharmaceutically acceptablesalt thereof:

wherein

-   -   R¹ and R² are both hydrido or R¹ and R² together with the atoms        to which they are bonded form a 5- to 8-membered ring containing        one, two or three heteroatoms in the ring that are oxygen,        sulfur or nitrogen.

R³ in formula I is an optionally substituted aryl or optionallysubstituted heteroaryl radical. When R³ is a substituted aryl orheteroaryl radical, a contemplated substituent is selected from thegroup consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl,aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl,aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl,aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl,alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, anaralkylthioaryl radical, the sulfoxide or sulfone of any of the thiosubstituents, and a fused ring structure comprising two or more 5- or6-membered rings selected from the group consisting of aryl, heteroaryl,carbocyclic and heterocyclic.

The substituent bonded to the aryl or heteroaryl radical of which the R³radical is comprised itself can be substituted with one or moresubstituents; i.e., the substituting substituent is optionallysubstituted. When that aryl or heteroaryl radical is substituted, andthe substituting moiety (group, substituent, or radical) is itselfsubstituted, the last-named substituent is independently selected fromthe group consisting of a cyano, perfluoroalkyl, trifluoromethoxy,trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl,aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol,hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino,heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl,heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy,cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy,aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo,hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl,aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl,arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl,hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy,alkoxycarbonylalkylthio, amino,

-   -   wherein the amino nitrogen is (i) unsubstituted, or (ii)        substituted with one or two substituents that are independently        selected from the group consisting of an alkyl, aryl,        heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl,        alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl,        heteroaralkanoyl and an alkanoyl group, or (iii) wherein the        amino nitrogen and two substituents attached thereto form a 5-        to 8-membered heterocyclo or heteroaryl ring containing zero to        two additional heteroatoms that are nitrogen, oxygen or sulfur        and which ring itself is (a) 5 unsubstituted or (b) substituted        with one or two groups independently selected from the group        consisting of an aryl, alkyl, heteroaryl, aralkyl,        heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl,        heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl,        benzofused heterocycloalkyl, hydroxyalkoxyalkyl,        aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused        heterocycloalkoxy, benzofused cycloalkylcarbonyl,        heterocycloalkylcarbonyl, and a cycloalkylcarbonyl group,        carbonylamino    -   wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii)        is the reacted amine of an amino acid, or (iii) substituted with        one or two radicals selected from the group consisting of an        alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl,        trifluoromethylalkyl, heterocycloalkyl, benzofused        heterocycloalkyl, benzofused heterocycloalkyl, benzofused        cycloalkyl, and an N,N-dialkyl substituted alkylamino-alkyl        group, or (iv) the carboxamido nitrogen and two substituents        bonded thereto together form a 5- to 8-membered heterocyclo,        heteroaryl or benzofused heterocycloalkyl ring that is itself        unsubstituted or substituted with one or two radicals        independently selected from the group consisting of an alkyl,        alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy,        hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino        group,        -   wherein the amino nitrogen is (i) unsubstituted, or (ii)            substituted with one or two substituents that are            independently selected from the group consisting of alkyl,            aryl, and heteroaryl, or (iii) wherein the amino nitrogen            and two substituents attached thereto form a 5- to            8-membered heterocyclo or heteroaryl ring,            and an aminoalkyl group    -   wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii)        substituted with one or two substituents independently selected        from the group consisting of an alkyl, aryl, aralkyl,        cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl        group, or (iii) wherein the aminoalkyl nitrogen and two        substituents attached thereto form a 5- to 8-membered        heterocyclo or heteroaryl ring.

In preferred practice, R¹ and R² together with the atoms to which theyare bonded form a 6-membered ring.

An R³ radical preferably has a length that is greater than that of apentyl group [a —(CH₂)₄CH₃ chain] and more preferably greater than aboutthat of a hexyl group [a —(CH₂)₅CH₃ chain]. An R³ radical preferably hasa length that is less than that of an icosyl group [a —(CH₂)₁₉CH₃chain], and more preferably a length that is less than that of a stearylgroup [a —(CH₂)₁₇CH₃ chain). A preferred R³ group contains two or more5- or 6-membered rings. A contemplated R³ group, when rotated about anaxis drawn through the SO₂-bonded 1-position and the substituent-bonded4-position of a 6-membered ring or the SO₂-bonded 1-position andsubstituent-bonded 3-or 4-position of a 5-membered ring, defines athree-dimensional volume whose widest dimension has the width in adirection transverse to that axis to rotation of about one furanyl ringto about two phenyl rings.

It is also preferred that a R³ radical be a single-ringed aryl orheteroaryl group that is 5- or 6-membered, and is itself substituted atits own 4-position when a 6-membered ring or at its own 3- or 4-positionwhen a 5-membered ring with an optionally substituted substituentselected from the group consisting of one other single-ringed aryl orheteroaryl group, a C₃-C₁₄ alkyl group, a N-piperidyl group, aN-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridylgroup, a phenylazo group and a benzamido group. The substituent of the5- or 6-membered aryl or heteroaryl group can itself be substituted asdiscussed before.

A preferred compound for use in a contemplated process has a structurethat corresponds to formula II, below, or a pharmaceutically acceptablesalt thereof:

wherein

-   -   R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R¹⁵        where W is O or S and R¹⁵ is selected from the group consisting        of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy,        ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein        the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two substituents independently selected from the        group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl,        C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii)        wherein the amino C₁-C₆-alkyl nitrogen and two substituents        attached thereto form a 5- to 8-membered heterocyclo or        heteroaryl ring;    -   m is zero, 1 or 2;    -   n is zero, 1 or 2;    -   p is zero, 1 or 2;    -   the sum of m+n+p=1, 2, 3 or 4;    -   (a) one of X, Y and Z is selected from the group consisting of        C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two        of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹ or    -   (b) X and Z or Z and Y together constitute a moiety that is        selected from the group consisting of NR⁶C(O), NR⁶S(O),        NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining        one of X, Y and Z being CR⁸R⁹, or    -   (c) n is zero and X, Y and Z together constitute a moiety        selected from the group consisting of        wherein wavy lines are bonds to the atoms of the depicted ring;    -   R⁶ and R^(6′) are independently selected from the group        consisting of hydrido, C₁-C₆-alkanoyl, C₆-aryl-C₁-C₆-alkyl,        aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)—C₁-C₆-alkyl, C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl,        C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl,        C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, C₆-aryl,        C₅-C₆-heterocyclo, C₅-C₆-heteroaryl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₆-aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,        heteroarylthio-C₁-C₆-alkyl, C₆-arylsulfonyl,        C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl,        carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl,        aminocarbonyl, C₁-C₆-alkyliminocarbonyl, C₆-aryliminocarbonyl,        C₅-C₆-heterocycloiminocarbonyl, C₆-arylthio-C₁-C₆-alkyl,        C₁-C₆-alkylthio-C₁-C₆-alkyl, C₆-arylthio-C₃-C₆-alkenyl,        C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl,        halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl,        thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl,        NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, an aminocarbonyl        wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group,        hydroxyaminocarbonyl, an aminosulfonyl group wherein the        aminosulfonyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two radicals independently selected from the group        consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and        a C₁-C₆-alkanoyl group, an amino-C₁-C₆-alkylsulfonyl group        wherein the amino-C₁-C₆-alkylsulfonyl nitrogen is (i)        unsubstituted or (ii) substituted with one or two radicals        independently selected from the group consisting of C₁-C₆-alkyl,        ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group and        an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen        is (i) unsubstituted or (ii) substituted with one or two        radicals independently selected from the group consisting of        C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a        C₁-C₆-alkanoyl group;    -   R⁷ is selected from the group consisting of a arylalkyl, aryl,        heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,        C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl        group;    -   R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the        group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, aryl,        ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl,        C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl        cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,        hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl,        hydroxycarbonylar-C₁-C₆-alkyl; aminocarbonyl-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the        carbon to which they are bonded form a carbonyl group, or        wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with        the atoms to which they are bonded form a 5- to 8-membered        carbocyclic ring, or a 5- to 8-membered heterocyclic ring        containing one or two heteroatoms that are nitrogen, oxygen, or        sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and        R¹¹ is hydroxy;    -   R¹² and R^(12′) are independently selected from the group        consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl,        heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,        thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,        hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl,        aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl;    -   R¹³ is selected from the group consisting of a hydrido, benzyl,        phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group; and    -   G—A—R—E—Y is a substituent that preferably has a length greater        than that of a pentyl group, and more preferably has a length        greater than that of a hexyl group. The substituent G—A—R—E—Y        preferably has a length that is less than that of an icosyl        group, and is more preferably less than that of a stearyl group.        In this substituent:        -   G is an aryl or heteroaryl group;        -   A is selected from the group consisting of            -   (1) —O—;            -   (2) —S—;            -   (3) —NR¹⁷—;            -   (4) —CO—N(R¹⁷) or —N(R¹⁷)—CO—, wherein R¹⁷ is hydrogen,                C₁-C₄-alkyl, or phenyl;            -   (5) —CO—O— or —O—CO—;            -   (6) —O—CO—O—;            -   (7) —HC═CH—;            -   (8) —NH—CO—NH—;            -   (9) —C≡C—;            -   (10) —NH—CO—O— or —O—CO—NH—;            -   (11) —N═N—;            -   (12) —NH—NH—; and            -   (13) —CS—N(R¹⁸)— or —N(R¹⁸)—CS—, wherein R¹⁸ is hydrogen                C₁-C₄-alkyl, or phenyl; or            -   (14) A is absent and G is bonded directly to R;        -   R is a moiety selected from the group consisting of alkyl,            alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,            aralkyl, heteroaralkyl, heterocycloalkylalkyl,            cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl,            aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl,            heteroarylthioalkyl, cycloalkylthioalkyl, and a            heterocycloalkylthioalkyl group wherein the aryl or            heteroaryl or cycloalkyl or heterocycloalkyl substituent            is (i) unsubstituted or (ii) substituted with one or two            radicals selected from the group consisting of a halo,            alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,            trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy,            C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl,            hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl,            alkanoylamino, and a alkoxycarbonyl group, and R is other            than alkyl or alkoxyalkyl when A is —O— or —S—;        -   E is selected from the group consisting of            -   (1) —CO(R¹⁹)— or —(R¹⁹)CO—, wherein R¹⁹ is a                heterocycloalkyl, or a cycloalkyl group;            -   (2) —CONH— or —HNCO—; and            -   (3) —CO—;            -   (4) —SO₂—R¹⁹— or —R¹⁹—SO₂—;            -   (5) —SO₂—;            -   (6) —NH—SO₂— or —SO₂—NH—; or            -   (7) E is absent and R is bonded directly to Y; and        -   Y is absent or is selected from the group consisting of a            hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl,            cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy,            heteroaryloxy, heteroaralkyl, perfluoroalkoxy,            perfluoroalkylthio, trifluoromethylalkyl, alkenyl,            heterocycloalkyl, cycloalkyl, trifluoromethyl,            alkoxycarbonyl, and a aminoalkyl group, wherein the aryl or            heteroaryl or heterocycloalkyl group is (i) unsubstituted            or (ii) substituted with one or two radicals independently            selected from the group consisting of an alkanoyl, halo,            nitro, aralkyl, aryl, alkoxy, and an amino group wherein the            amino nitrogen is (i) unsubstituted or (ii) substituted with            one or two groups independently selected from hydride,            alkyl, and an aralkyl group.

A particularly preferred compound for use in a contemplated processcorresponds in structure to formula III, below, or a pharmaceuticallyacceptable salt thereof:

wherein

-   -   m, n, p, X, Z, Y and R¹⁴ are as defined above for formula II,        and the R³ radical that is defined below is a sub-set of the        previously discussed G—A—R—E—Y substituents.

Thus, R³ is a radical that is comprised of a single-ringed aryl orheteroaryl group that is 5- or 6-membered, and is itself substituted atits own 4-position when a 6-membered ring and at its own 3- or4-position when a 5-membered ring with a substituent selected from thegroup consisting of a thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy,4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy,4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy,4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy,4-(trifluoromethylthio)-phenoxy, 4-(trifluoromethylthio)-thiophenoxy,4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy,(2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy,4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy,3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy,4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy,3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy,4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy,6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy,5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy,N-piperidyl, N-piperazinyl and a 4-benzyloxyphenoxy group.

A more particularly preferred compound for use in a contemplated processhas a structure that corresponds to formula IV, below, or apharmaceutically acceptable salt thereof:

wherein R³ is as defined above for formula I, S more preferably asdefined for formula II (wherein this R³ group is the G—A—R—E—Ysubstituent), and more preferably still as defined for formula III, and

-   -   Z is selected group the group consisting of O, S, NR⁶, SO, SO₂,        and NSO₂R⁷,    -   wherein R⁶ is selected from the group consisting of hydrido,        C₁-C₅-alkyl, C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl,        C₃-C₅-alkenyl, C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl,        heteroaryl-C₁-C₆-alkyl, C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl,        C₁-C₅-alkoxy C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkylcarbonyl        or NR⁸R⁹—C₁-C₅-alkyl wherein R⁸ and R⁹ are independently        hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl or        aryl-C₁-C₅-alkoxycarbonyl, or NR⁸R⁹ together form a heterocyclic        ring containing 5- to 8-atoms in the ring; and    -   R⁷ is selected from the group consisting of an arylalkyl, aryl,        heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,        C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl        group.

A still more preferred group of compounds for use in a contemplatedprocess correspond in structure to formula V, below, or apharmaceutically acceptable salt thereof:

wherein

-   -   Z is as previously defined in formula IV;    -   W and Q are independently oxygen (O), NR⁶ or sulfur (S), and R⁶        is as defined in formula IV; and    -   q is zero or one such that when q is zero, the trifluoromethyl        group is bonded directly to the depicted phenyl ring.

The use of a compound of formulas I-V, or a pharmaceutically acceptablesalt of one of those compounds is contemplated in a before-describedprocess. In addition, the compounds of formulas II, III, IV and V, andtheir pharmaceutically acceptable salts are contemplated compounds ofthis invention.

The present invention also contemplates a precursor or intermediatecompound that is useful in preparing a compound of formulas I-V. Such anintermediate compound corresponds in structure to formula VI, below:

wherein m, n, p, X, Z and Y are as defined above for formula II, g iszero, 1 or 2 and R²⁴ is R³ as defined in formulas I, III or IV, is thesubstituent G—A—R—E—Y of formula II (formula VIA) or is R^(3′), an arylor heteroaryl group that is substituted with a coupling substituentreactive for coupling with another moiety (formula VIB), such as anucleophilically displaceable leaving group, D.

Exemplary nucleophilically displaceable leaving groups, D, include ahalo (fluoro, chloro, bromo, or idodo) nitro, azido, phenylsulfoxido,aryloxy, C₁-C₆-alkoxy, a C₁-C₆-alkylsulfonate or arylsulfonate group anda trisubstituted ammonium group in which the three substituents areindependently aryl, ar-C₁-C₆-alkyl or C₁-C₆-alkyl.

R²⁰ is (a) —O—R²¹, where R²¹ is selected from the group consisting of ahydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceuticallyacceptable cation, or (b) —NH—O—R²² wherein R²² is a selectivelyremovable protecting group such as a 2-tetrahydropyranyl, C₁-C₆-acyl,aroyl, benzyl, p-methoxybenzyloxycarbonyl (MOZ), benzyloxycarbonyl,C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxy-CH₂—, C₁-C₆-alkoxy-C₁-C₆-alkoxy-CH₂—,trisubstituted silyl group or o-nitrophenyl group, peptide synthesisresin and the like. Trisubstituted silyl group is substituted withC₁-C₆-alkyl, aryl, or ar-C₁-C₆-alkyl.

A particularly preferred precursor intermediate to an intermediatecompound of formula VI is an intermediate compound of formula VII

wherein m, n, p, g, X, Z, Y, D and R²⁰ are as defined above for formulaVI.

Among the several benefits and advantages of the present invention arethe provision of compounds and compositions effective as inhibitors ofmatrix metalloproteinase activity, the provision of such compounds andcompositions that are effective for the inhibition of metalloproteinasesimplicated in diseases and disorders involving uncontrolled breakdown ofconnective tissue.

More particularly, a benefit of this invention is the provision of acompound and composition effective for selectively inhibiting certainmetalloproteinases, such as one or more of MMP-2, MMP-9 and MMP-13,associated with pathological conditions such as, for example, rheumatoidarthritis, osteoarthritis, septic arthritis, corneal, epidermal orgastric ulceration, tumor metastasis, invasion or angiogenesis,periodontal disease, proteinuria, Alzheimer's Disease, coronarythrombosis and bone disease.

An advantage of the invention is the provision of compounds,compositions and methods effective for treating such pathologicalconditions by selective inhibition of a metalloproteinase such as MMP-2,MMP-9 or MMP-13 associated with such conditions with minimal sideeffects resulting from inhibition of other metalloproteinases, such asMMP-1, whose activity is necessary or desirable for normal bodyfunction.

Yet another advantage of the invention is the provision of a process forpreparing such compounds.

Another benefit is the provision of a method for treating a pathologicalcondition associated with abnormal matrix metalloproteinase activity.

A further advantage of the invention is the provision of a process forpreparing such compositions.

Still further benefits and advantages of the invention will be apparentto the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, it has been discovered thatcertain aromatic sulfone hydroxamic acids (hydroxamates) are effectivefor inhibition of matrix metalloproteinases (“MMPs”) believed to beassociated with uncontrolled or otherwise pathological breakdown ofconnective tissue. In particular, it has been found that these certainaromatic sulfone hydroxamates are effective for inhibition of one ormore enzymes such as MMP-2, MMP-9 and MMP-13, which can be particularlydestructive to tissue if present or generated in abnormal quantities orconcentrations, and thus exhibit a pathological activity. Included inthat pathological activity is the assistance of tumors and tumor cellsin the process of penetrating basement membrane, and developing a new orimproved blood supply; i.e., angiogenesis.

Moreover, it has been discovered that these aromatic sulfonehydroxamates are selective in the inhibition of one or more of MMP-2,MMP-9 and MMP-13 without excessive inhibition of other collagenasesessential to normal bodily function such as tissue turnover and repair.More particularly, it has been found that a contemplated aromaticsulfone hydroxamate of the invention, or a pharmaceutically acceptablesalt thereof, is particularly active in inhibiting of one or more ofMMP-2, MMP-9 and MMP-13 in an in vitro assay that is predictive of invivo activity. In addition, while being selective for one or more ofMMP-2, MMP-9 and MMP-13, a contemplated aromatic sulfone hydroxamate, orits salt, has a limited or minimal in vitro inhibitory effect on MMP-1.

There is thus a substantial difference in the activity of a compoundused in a contemplated process toward one or more of MMP-2, MMP-9 andMMP-13 and MMP-1. This substantial difference is assayed using the invitro inhibition assay discussed in the examples. A substantialdifference in activity corresponds to a compound exhibiting an IC₅₀value against one or more of MMP-2, MMP-9 and MMP-13 that is about 0.1times that of the compound against MMP-1, and more preferably 0.01 timesthat against MMP-1 and most preferably 0.001 times that against MMP-1,or more. Indeed, some compounds exhibit selectivity differences measuredby IC₅₀ values that exceed the bounds of the assay at the number100,000-fold. These selectivities are illustrated in the InhibitionTables hereinafter.

Put differently, a contemplated compound can inhibit the activity ofMMP-2 compared to MMP-9 or MMP-13 and MMP-1. Similarly, a contemplatedcompound can inhibit the activity of MMP-13 and MMP-2, while exhibitingless inhibition against MMP-1 and MMP-9. In addition, a contemplatedcompound can inhibit the activity of a MMP enzyme, while having less ofan effect on tumor necrosis factor release.

The advantages of the selectivity of a contemplated compound can beappreciated, without wishing to be bound by theory, by considering thetherapeutic uses the compounds. For example, inhibition of MMP-1 issuggested to be undesirable due to its role as a housekeeping enzyme,helping to maintain normal connective tissue turnover and repair.Inhibition of MMP-1 can lead to toxicities or side effects such as suchas joint or connective tissue deterioration and pain. On the other hand,MMP-13 has been suggested to be intimately involved in the destructionof joint components in diseases such as osteoarthritis. Thus, potent andselective inhibition of MMP-13 compared with inhibition MMP-1 is highlydesirable because a MMP-13 inhibitor can have a positive effect ondisease progression in a patient in addition to having ananti-inflammatory effect.

Inhibition of MMP-2 and MMP-9 can be desirable for inhibition of tumorgrowth, metastasis, invasion and/or angiogenesis. A profile of selectiveinhibition of MMP-2 and MMP-9 relative to MMP-1 can provide atherapeutic advantage.

Yet another advantage of a contemplated compound is the selectivity withrespect to tumor necrosis factor release and/or tumor necrosis factorreceptor release that provides the physician with another factor to helpselect the best drug for a particular patient. While not wishing to bebound by theory, it is believed that there are several factors to thistype of selectivity to be considered.

The first is that presence of tumor necrosis factor can be desirable forthe control of cancer in the organism, so long as TNF is not present ina toxic excess. Thus, uncontrolled inhibition of release of TNF can becounterproductive and actually can be considered an adverse side effecteven in cancer patients. In addition, selectivity with respect toinhibition of the release of the tumor necrosis factor receptor can alsobe desirable. The presence of that receptor can be desirable formaintaining a controlled tumor necrosis level in the mammal by bindingexcess TNF.

A contemplated selective MMP inhibitor compound useful in a contemplatedprocess can be administered to by various routes and provide adequatetherapeutic blood levels of enzymatically active inhibitor. A compoundcan be administered, for example, by the oral (IG, PO) or intravenous(IV) routes. Oral administration is advantageous if the patient isambulatory, not hospitalized, physically able and sufficientlyresponsible to take drug at the required intervals. This is true even ifthe person is being treated with more than one drug for one or morediseases. On the other hand, IV drug administration is an advantage in ahospital setting wherein the dose and thus the blood levels can wellcontrolled. A contemplated inhibitor can also be formulated for IMadministration if desired. This route of administration can be desirablefor the administration of prodrugs or regular drug delivery to patientsthat are either physically weak or have a poor compliance record orrequire constant drug blood levels.

Thus, in one embodiment, the present invention is directed to atreatment process that comprises administering a contemplated aromaticsulfone hydroxamic acid metalloprotease inhibitor, or a pharmaceuticallyacceptable salt thereof, in an effective amount to a host mammal havinga condition associated with pathological matrix metalloproteaseactivity. A contemplated aromatic sulfone hydroxamate inhibitor compounduseful in such a process inhibits the activity of one or more of MMP-2,MMP-9 and MMP-13, and exhibits substantially less inhibitory activityagainst at least MMP-1 in the in vitro assay noted above and discussedin detail hereinbelow. An aromatic sulfone hydroxamate inhibitorcompound for use in a contemplated process corresponds in structure toformula I, below:

wherein

-   -   In one embodiment, R¹ and R² are both hydrido. In another        embodiment, R¹ and R² together with the atoms to which they are        bonded form a 5- to 8-membered ring containing one, two or three        heteroatoms in the ring that are oxygen, sulfur or nitrogen.

It is preferred that R¹ and R² together with the atoms to which they arebonded form a five- to eight-membered ring that contains one or twoheteroatoms in the ring, although R¹ and R² together with the atoms towhich they are bonded form a 5- to 8-membered ring containing one, twoor three heteroatoms. The heterocyclic ring can itself also besubstituted with up to six C₁-C₆-alkyl groups or groups that comprise aanother 5- to 8-membered carbocyclic or heterocyclic ring, an aminogroup, or contain one or two oxo(carbonyl) groups.

R³ in formula I is an optionally substituted aryl or optionallysubstituted heteroaryl radical. That R³ radical is selected from thegroup consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl,aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl,arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl,arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl,alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, thesulfoxide or sulfone of any of the thio substituents, and a fused ringstructure comprising two or more 5- or 6-membered rings selected fromthe group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.

The substituent of which R³ is comprised itself is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of a cyano, perfluoroalkyl, trifluoromethylalkyl,hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy,arylthio, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl,cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino,cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio,aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo,hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl,aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl,arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl,hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy,alkoxycarbonylalkylthio, amino,

-   -   wherein the amino nitrogen is (i) unsubstituted, or (ii)        substituted with one or two substituents that are independently        selected from the group consisting of an alkyl, aryl,        heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl,        alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl,        heteroaralkanoyl and an alkanoyl group, or (iii) wherein the        amino nitrogen and two substituents attached thereto form a 5-        to 8-membered heterocyclo or heteroaryl ring containing zero to        two additional heteroatoms that are nitrogen, oxygen or sulfur        and which ring itself is (a) unsubstituted or (b) substituted        with one or two groups independently selected from the group        consisting of an aryl, alkyl, heteroaryl, aralkyl,        heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl,        heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl,        benzofused heterocycloalkyl, hydroxyalkoxyalkyl,        aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused        heterocycloalkoxy, benzofused cycloalkylcarbonyl,        heterocycloalkylcarbonyl, and a cycloalkylcarbonyl group,        carbonylamino    -   wherein the carboxamido nitrogen is (i) unsubstituted, or (ii)        is the reacted amine of an amino acid, or (iii) substituted with        one or two radicals selected from the group consisting of an        alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl,        trifluoromethylalkyl, heterocycloalkyl, benzofused        heterocycloalkyl, benzofused heterocycloalkyl, benzofused        cycloalkyl, and an N,N-dialkyl substituted alkylamino-alkyl        group, or (iv) the carboxamido nitrogen and two substituents        bonded thereto together form a 5- to 8-membered heterocyclo,        heteroaryl or benzofused heterocycloalkyl ring that is itself        unsubstituted or substituted with one or two radicals        independently selected from the group consisting of an alkyl,        alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy,        hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino        group,        -   wherein the amino nitrogen is (i) unsubstituted, or (ii)            substituted with one or two substituents that are            independently selected from the group consisting of alkyl,            aryl, and heteroaryl, or (iii) wherein the amino nitrogen            and two substituents attached thereto form a 5- to            8-membered heterocyclo or heteroaryl ring,            and an aminoalkyl group    -   wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii)        substituted with one or two substituents independently selected        from the group consisting of an alkyl, aryl, aralkyl,        cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl        group, or (iii) wherein the aminoalkyl nitrogen and two        substituents attached thereto form a 5- to 8-membered        heterocyclo or heteroaryl ring. A compound of formula I can also        be used in the form of a pharmaceutically acceptable salt.

The R³ radical has a length that is greater than that of a pentyl group[a —(CH₂)₄CH₃ chain], and is more preferably greater than about thelength of a hexyl group [a —(CH₂)₅CH₃ chain]. A R³ group has a lengththat is less than that of an icosyl group [eicosyl; a —(CH₂)₁₉CH₃chain), and more preferably, a length that is less than that of astearyl group [a —(CH₂)₁₇CH₃ chain). When rotated about an axis drawnthrough the SO₂-bonded 1-position and the substituent-bonded 4-positionof a 6-membered ring or the SO₂-bonded 1-position and substituent-bonded3- or 4-position of a 5-membered ring, a contemplated R³ radical definesa three-dimensional volume whose widest dimension has the width of aboutone furanyl ring to about two phenyl rings in a direction transverse tothat axis to rotation.

Where the SO₂-linked R³ radical is 4-phenoxyphenyl for purposes ofillustration, a contemplated compound can be viewed as aphenoxyphenylsulfone derivative of the desired 5- to 8-membered ringN-hydroxycarboxamide. Exemplary compounds can therefore be named;

-   -   N-hydroxy-1-methyl-[4-(phenoxyphenylsulfonyl)]-4-piperidinecarboxamide,    -   N-hydroxy-[4-(phenoxyphenylsulfonyl)]tetrahydro-2H-pyran-4-carboxamide,    -   N-hydroxy-1-methyl-[2,6-dioxo-4-(phenoxyphenylsulfonyl)]-4-piperidinecarboxamide,    -   N-hydroxy-2,2-dimethyl-[5-(phenoxyphenylsulfonyl)]-1,3-dioxane-5-carboxamide,    -   N-hydroxy-1,2-dimethyl-6-oxo-[4-(phenoxyphenylsulfonyl)]-4-piperidinecarboxamide,    -   N-hydroxy-2,2,6,6,tetramethyl-[4-(phenoxyphenylsulfonyl)]-4-piperidinecarboxamide,    -   N-hydroxy-1,3-dimethyl-[5-(phenoxyphenylsulfonyl)]-hexahydro-5-pyrimidinecarboxamide,    -   2-amino-N-hydroxy-[5-(phenoxyphenylsulfonyl)]-1,4,5,6-tetrahydro-5-pyrimidinecarboxamide,    -   N-hydroxy-1,1-dioxo-[4-(phenoxyphenylsulfonyl)]-1(λ6),2,6-thiadizinane-4-carboxamide,    -   N-hydroxy-2-oxo-[5-(phenoxyphenylsulfonyl)]-hexahydro-5-pyrimidinecarboxamide,    -   N-hydroxy-[2-(phenoxyphenylsulfonyl)]tetrahydro-2-furancarboxamide,    -   N-hydroxy-1-methyl-[2-(phenoxyphenylsulfonyl)]-2-pyrrolidinecarboxamide,    -   N-hydroxy-2-methyl-[4-(phenoxyphenylsulfonyl)]-4-piperidinecarboxamide,    -   N-hydroxy-[3-(phenoxyphenylsulfonyl)]-8-azabicyclo[3.2.1]octane-3-carboxamide,    -   N-hydroxy-1,1-dioxo-[4-(phenoxyphenylsulfonyl)]-hexahydro-1(lambda6)-thiopyran-4-carboxamide,    -   N-hydroxy-[3-(phenoxyphenylsulfonyl)]tetrahydro-3-furancarboxamide,    -   N-hydroxy-[3-(phenoxyphenylsulfonyl)]-3-pyrrolidinecarboxamide,    -   N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,        monohydrochloride,    -   N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,        monomethanesulfonate,    -   tetrahydro-N-hydroxy-4-[[4-[4-[(trifluoromethyl]phenoxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide,    -   N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide,        hydrochloride,    -   N-hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-trifluoromethyl)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide,        dihydrochloride,    -   N-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide,        dihydrochloride,    -   hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide,        dihydrochloride,    -   N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl}-4-piperidinecarboxamide,        monohydrochloride,    -   N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl}-4-piperidinecarboxamide,        monohydrochloride,    -   N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,        monohydrochloride,    -   1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,        monohydrochloride, and the like.

Several exemplary R¹ and R² groups that together form a contemplatedheterocyclic ring are shown in the Tables that follow hereinafter, aswell as in the descriptions of those 5- to 8-membered rings and thespecific Examples, as are several contemplated aromatic sulfonehydroxamic acid compounds.

In more preferred practice, R¹ and R² of formula I together with theatom to which they are bonded form a 5- to 8-membered ring that containsone, two or three heteroatoms. Most preferably, that ring is a6-membered ring that contains one heteroatom located at the 4-positionrelative to the position at which the SO₂ group is bonded. Otherpreferred compounds for use in a contemplated process correspond instructure to one or more of formulas II, III, IV or V, which arediscussed hereinafter.

In one embodiment, a preferred compound used in a contemplated processhas a structure that corresponds to formula II, below:

wherein

-   -   R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R¹⁵        where W is O or S and R¹⁵ is selected from the group consisting        of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy,        ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein        the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two substituents independently selected from the        group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl,        C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii)        wherein the amino C₁-C₆-alkyl nitrogen and two substituents        attached thereto form a 5- to 8-membered heterocyclo or        heteroaryl ring;    -   m is zero, 1 or 2;    -   n is zero, 1 or 2;    -   p is zero, 1 or 2;    -   the sum of m+n+p=1, 2, 3 or 4;    -   (a) one of X, Y and Z is selected from the group consisting of        C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two        of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹, or    -   (b) X and Z or Z and Y together constitute a moiety that is        selected from the group consisting of NR⁶C(O), NR⁶S(O),        NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining        one of X, Y and Z being CR⁸R⁹, or    -   (c) n is zero and X, Y and z together constitute a moiety        selected from the group consisting of        wherein wavy lines are bonds to the atoms of the depicted ring;    -   R⁶ and R^(6′) are independently selected from the group        consisting of hydrido, C₁-C₆-alkanoyl, C₆-aryl-C₁-C₆-alkyl,        aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)—C₁-C₆-alkyl, C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl,        C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl,        C₃-C₅-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, C₆-aryl,        C₅-C₆-heterocyclo, C₅-C₆-heteroaryl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₆-aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,        heteroarylthio-C₁-C₆-alkyl, C₆-arylsulfonyl,        C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl,        carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl,        aminocarbonyl, C₁-C₆-alkyliminocarbonyl, C₆-aryliminocarbonyl,        C₅-C₆-heterocycloiminocarbonyl, C₆-arylthio-C₁-C₆-alkyl,        C₁-C₆-alkylthio-C₁-C₆-alkyl, C₆-arylthio-C₃-C₆-alkenyl,        C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl,        halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl,        thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl,        NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, an aminocarbonyl        wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group,        hydroxyaminocarbonyl, an aminosulfonyl group wherein the        aminosulfonyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two radicals independently selected from the group        consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and        a C₁-C₆-alkanoyl group, an amino-C₁-C₆-alkylsulfonyl group        wherein the amino-C₁-C₆-alkylsulfonyl nitrogen is (i)        unsubstituted or (ii) substituted with one or two radicals        independently selected from the group consisting of C₁-C₆-alkyl,        ar-C₁-C₆-alkyl, C₃-C₅-cycloalkyl and a C₁-C₆-alkanoyl group and        an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen        is (i) unsubstituted or (ii) substituted with one or two        radicals independently selected from the group consisting of        C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a        C₁-C₆-alkanoyl group;    -   R⁷ is selected from the group consisting of a benzyl, phenyl,        C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group;    -   R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the        group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, aryl,        ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl,        C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl        cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,        hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl,        hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the        carbon to which they are bonded form a carbonyl group, or        wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with        the atoms to which they are bonded form a 5- to 8-membered        carbocyclic ring, or a 5- to 8-membered heterocyclic ring        containing one or two heteroatoms that are nitrogen, oxygen, or        sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and        R¹¹ is hydroxy;    -   R¹² and R^(12′) are independently selected from the group        consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl,        heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,        thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,        hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl,        aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl;    -   R¹³ is selected from the group consisting of a hydrido, benzyl,        phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group; and    -   G—A—R—E—Y is a substituent that preferably has a length greater        than that of a pentyl group, and more preferably has a length        greater than that of a hexyl group. The substituent G—A—R—E—Y        preferably has a length that is less than that of an icosyl        group, and is more preferably less than that of a stearyl group.        In this substituent:        -   G is an aryl or heteroaryl group;        -   A is selected from the group consisting of            -   (1) —O—;            -   (2) —S—;            -   (3) —NR¹⁷—;            -   (4) —CO—N(R¹⁷) or —N(R¹⁷)—CO—, wherein R¹⁷ is hydrogen,                C₁-C₄-alkyl, or phenyl;            -   (5) —CO—O— or —O—CO—;            -   (6) —O—CO—O—;            -   (7) —HC═CH—;            -   (8) —NH—CO—NH—;            -   (9) —C≡C—;            -   (10) —NH—CO—O— or —O—CO—NH—;            -   (11) —N═N—;            -   (12) —NH—NH—; and            -   (13) —CS—N(R¹⁸)— or —N(R¹⁸)—CS—, wherein R¹⁸ is hydrogen                C₁-C₄-alkyl, or phenyl; or            -   (14) A is absent and G is bonded directly to R;        -   R is a moiety selected from the group consisting of alkyl,            alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,            aralkyl, heteroaralkyl, heterocycloalkylalkyl,            cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl,            aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl,            heteroarylthioalkyl, cycloalkylthioalkyl, and a            heterocycloalkylthioalkyl group wherein the aryl or            heteroaryl or cycloalkyl or heterocycloalkyl substituent            is (i) unsubstituted or (ii) substituted with one or two            radicals selected from the group consisting of a halo,            alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,            trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy,            C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl,            hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl,            alkanoylamino, and a alkoxycarbonyl group, and R is other            than alkyl or alkoxyalkyl when A is —O— or —S—;        -   E is selected from the group consisting of            -   (1) —CO(R¹⁹)— or —(R¹⁹)CO—, wherein R¹⁹ is a                heterocycloalkyl, or a cycloalkyl group;            -   (2) —CONH— or —HNCO—; and            -   (3) —CO—;            -   (4) —SO₂—R¹⁹— or —R¹⁹—SO₂—;            -   (5) —SO₂—;            -   (6) —NH—SO₂— or —SO₂—NH—; or            -   (7) E is absent and R is bonded directly to Y; and        -   Y is absent or is selected from the group consisting of a            hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl,            cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy,            heteroaryloxy, heteroaralkyl, perfluoroalkoxy,            perfluoroalkylthio, trifluoromethylalkyl, alkenyl,            heterocycloalkyl, cycloalkyl, trifluoromethyl,            alkoxycarbonyl, and a aminoalkyl group, wherein the aryl or            heteroaryl or heterocycloalkyl group is (i) unsubstituted            or (ii) substituted with one or two radicals independently            selected from the group consisting of an alkanoyl, halo,            nitro, aralkyl, aryl, alkoxy, and an amino group wherein the            amino nitrogen is (i) unsubstituted or (ii) substituted with            one or two groups independently selected from hydrido,            alkyl, and an aralkyl group.

The substituent —G —A—R—E—Y preferably contains two to four carbocyclicor heterocyclic rings, including the aryl or heteroaryl group, G. Morepreferably, each of those rings is 6-membered. Additional separatepreferences for a compound of formula II include: (a) that A is —O— or—S—, (b) R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group,(c) E is absent, and (d) Y is selected from the group consisting ofhydrido, an alkyl, alkoxy, perfluoroalkoxy and a perfluoroalkylthiogroup.

A more preferred compound for use in a contemplated process has astructure that corresponds to formula III, below:

wherein R³ is a single-ringed aryl or heteroaryl group that is 5- or6-membered, and is itself substituted at its own 4-position when a6-membered ring and at its own 3- or 4-position when a 5-membered ringwith a substituent selected from the group consisting of a thiophenoxy,4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy,3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy,4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxyphenoxy,4-trifluoromethylphenoxy, 4-(trifluoromethylthio)phenoxy,4-(trifluoromethylthio)thiophenoxy, 4-chloro-3-fluorophenoxy,4-isopropoxyphenoxy, 4-isopropylphenoxy,(2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy,4-chloro-3-methylphenoxy, 3-methyl-phenoxy, 4-ethoxyphenoxy,3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy,4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy,3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy,4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy,6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy,5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and a4-benzyloxyphenoxy group;

-   -   R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R¹⁵        where w is O or S and R¹⁵ is selected from the group consisting        of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy,        ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein        the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two substituents independently selected from the        group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl,        C₁-C₆-alkoxycarbonyl, and a C₁-C₆-alkanoyl radical, or (iii)        wherein the amino C₁-C₆-alkyl nitrogen and two substituents        attached thereto form a 5- to 8-membered heterocyclo or        heteroaryl ring;    -   m is zero, 1 or 2;    -   n is zero, 1 or 2;    -   p is zero, 1 or 2;    -   the sum of m+n+p=1, 2, 3 or 4;    -   (a) one of X, Y and Z is selected from the group consisting of        C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two        of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹ or    -   (b) X and Z or Z and Y together constitute a moiety that is        selected from the group consisting of NR⁶ C(O), NR⁶S(O),        NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining        one of X, Y and Z being CR⁸R⁹, or    -   (c) n is zero and X, Y and Z together constitute a moiety        selected from the group consisting of        wherein wavy lines are bonds to the atoms of the depicted ring;    -   R⁶ and R^(6′) are independently selected from the group        consisting of hydrido, C₁-C₆-alkanoyl, C₆-aryl-C₁-C₆-alkyl,        aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)—C₁-C₆-alkylC₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl,        C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆ alkyl, C₃-C₆-cycloalkyl,        C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, C₆-aryl,        C₅-C₆-heterocyclo, C₅-C₆-heteroaryl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₆-aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,        heteroarylthio-C₁-C₆-alkyl, C₆-arylsulfonyl,        C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl,        carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl,        aminocarbonyl, C₁-C₆-alkyliminocarbonyl, C₆-aryliminocarbonyl,        C₅-C₆-heterocycloiminocarbonyl, C₆-arylthio-C₁-C₆-alkyl,        C₁-C₆-alkylthio-C₁-C₆-alkyl, C₆-arylthio-C₃-C₆-alkenyl,        C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl,        halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl,        thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl,        NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, an aminocarbonyl        wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group,        hydroxyaminocarbonyl, an aminosulfonyl group wherein the        aminosulfonyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two radicals independently selected from the group        consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and        a C₁-C₆-alkanoyl group, an amino-C₁-C₆-alkylsulfonyl group        wherein the amino-C₁-C₆-alkylsulfonyl nitrogen is (i)        unsubstituted or (ii) substituted with one or two radicals        independently selected from the group consisting of C₁-C₆-alkyl,        ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group and        an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen        is (i) unsubstituted or (ii) substituted with one or two        radicals independently selected from the group consisting of        C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a        C₁-C₆-alkanoyl group;    -   R⁷ is selected from the group consisting of a benzyl, phenyl,        C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group;    -   R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the        group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, aryl,        ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl,        C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl        cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,        hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl,        hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the        carbon to which they are bonded form a carbonyl group, or        wherein R⁸ and R⁹ or R¹⁰ and R¹¹ or R⁸ and R¹⁰ together with the        atoms to which they are bonded form a 5- to 8-membered        carbocyclic ring, or a 5- to 8-membered heterocyclic ring        containing one or two heteroatoms that are nitrogen, oxygen, or        sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and        R¹¹ is hydroxy;

R¹² and R^(12′) are independently selected from the group consisting ofa hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroaralkyl,C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, cycloalkyl,cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl,aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl,heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide orsulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group whereinthe aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted withone or two radicals independently selected from the group consisting ofC₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl; and

-   -   R¹³ is selected from the group consisting of a hydrido, benzyl,        phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group. Again, the use of a compound of        formula III as a pharmaceutically acceptable salt is also        contemplated.

Preferences related to a compound of formula III that also apply to acompound of formula II include the following, which are independentlypreferred: (a) the sum of m+n+p=1 or 2, and more preferably 2; (b) Z isO, S or NR⁶; (c) R⁶ is selected from the group consisting ofC₃-C₆-cycloalkyl, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, aminosulfonyl,heteroaryl-C₁-C₆-alkyl, aryloxycarbonyl, and C₁-C₆-alkoxycarbonyl; and(d) m=n=zero, p=1, and Y is NR⁶. Another preference for a compound ofboth of formulas II and III is that R¹⁴ be hydrido, or that W of theC(W)R¹⁵ pro-drug form be O and R¹⁵ be a C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy,heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, or aryloxy group.

A still more preferred compound for use in a contemplated processcorresponds in structure to formula IV, below:

Here, R³ is as defined above as to formulas I, III and more preferablyas defined as to formula II (wherein the R³ radical is the substituentG—A—R—E—Y). Most preferably, R³ is as defined in formula III.

Z is selected group the group consisting of O, S, NR⁶, SO, SO₂, andNSO₂R⁷,

-   -   wherein R⁶ is selected from the group consisting of hydrido,        C₁-C₅-alkyl, C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl,        C₃-C₅-alkenyl, C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl,        heteroaryl-C₁-C₆-alkyl, C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl,        C₁-C₅-alkoxy C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkylcarbonyl        or NR⁸R⁹—C₁-C₅-alkyl wherein R⁸ and R⁹ are independently        hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl or        aryl-C₁-C₅-alkoxycarbonyl, or NR⁸R⁹ together form a heterocyclic        ring containing 5- to 8-atoms in the ring; and    -   R⁷ is selected from the group consisting of an arylalkyl, aryl,        heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,        C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl        group. Most preferably, Z is O or NR⁶. Here too, the use of a        compound of formula IV as a pharmaceutically acceptable salt is        contemplated.

A still more preferred group of contemplated compounds for use in acontemplated process correspond in structure to formula V, below;

wherein

-   -   Z is as previously defined for formula IV;    -   W and Q are independently oxygen (O), NR⁶ or sulfur (S), and R⁶        is as defined in formula IV; and    -   q is zero or one such that when q is zero, Q is absent and the        trifluoromethyl group is bonded directly to the depicted phenyl        ring. Here again, the use of a compound of formula IV as a        pharmaceutically acceptable salt is contemplated.

Particularly preferred compounds within the group defined by formula Vhave the structural formulas shown below:

Also particularly preferred are the following compounds:

Several particularly preferred compounds whose structures correspond toformulas I through V are illustrated in the Tables and examples providedhereinafter.

As was noted before, the compounds of formulas II, III, IV and V, andtheir pharmaceutically acceptable salts are themselves contemplatedcompounds of the invention.

In preferred practice, an SO₂-linked R³ radical is an aryl or heteroarylgroup that is a 5-or 6-membered single-ring that is itself substitutedwith one other single-ringed aryl or heteroaryl group or, with an alkylor alkoxy group having a chain length of 3 to about 16 carbon atoms (andmore preferably a length of up to about 14 carbon atoms), a phenoxygroup, a thiophenoxy [C₆H₅—S—] group, a phenylazo [C₆H₅—N₂—] group, aN-piperidyl [C₅H₁₀N—] group, a N-piperazyl [NC₄H₉N—] group or abenzamido [—NHC(O)C₆H₅] group. The SO₂-linked single-ringed aryl orheteroaryl R³ group here is substituted at its own 4-position when a6-membered ring and at its own 3- or 4-position when a 5-membered ring.

The SO₂-linked aryl or heteroaryl group of a R³ radical is preferablyitself substituted at the 4-position when a 6-membered ring or the 3- or4-position when a 5-membered ring. A particularly preferred substituentis a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo,N-piperidyl, N-piperazyl or benzamido group that is unsubstituted or canitself be substituted.

The 4- and 3-positions of rings discussed here are numbered from thesites of substituent bonding as compared to formalized ring numberingpositions used in heteroaryl nomenclature, as is discussed furtherhereinbelow. Here, single atoms such as halogen moieties (fluoro,chloro, bromo, or iodo) or substituents that contain one to a chainlength of about five atoms other than hydrogen such as phenyl, C₁-C₄alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl orcarboxyethyl groups are preferred, although longer substituents can beaccommodated up to a total length of an icosyl group.

Exemplary particularly preferred substituted SO₂-linked R³ radicalsinclude 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)phenyl,4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl],4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl,4-[(4′-trifluoromethylthio)thiophenyl]phenyl,4-[(4′-trifluoromethyl)phenoxy]phenyl,4-[(4′-trifluoromethyl)thiophenyl]phenyl,4-[(4′-trifluoromethoxy)phenoxy]phenyl,4-[(4′-trifluoromethoxy)thiophenyl]phenyl,4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and4-(benzamido)phenyl.

Inasmuch as a contemplated SO₂-linked aryl or heteroaryl radical of anR³ group is itself preferably substituted with a 6-membered ring, twonomenclature systems are used together herein for ease in understandingsubstituent positions. The first system uses position numbers for thering directly bonded to the SO₂-group, whereas the second system usesortho, meta or para for the position of one or more substituents of a6-membered ring bonded to a SO₂-linked aryl or heteroaryl radical.Although ortho, meta and para positional nomenclature is normally notused with aliphatic ring systems, it is believed more readily understoodfor describing the present compounds when used in conjunction with thenumerical system for the first ring bonded to the SO₂-group. When a R³radical is other than a 6-membered ring, substituent positions arenumbered from the position of linkage to the aromatic or heteroaromaticring. Formal chemical nomenclature is used in naming particularcompounds.

Thus, the 1-position of an above-discussed SO₂-linked aryl or heteroarylgroup is the position at which the SO₂-group is bonded to the ring. The4-and 3-positions of rings discussed here are numbered from the sites ofsubstituent bonding from the SO₂-linkage as compared to formalized ringnumbering positions used in heteroaryl nomenclature.

When examined along its longest chain of atoms, an R³ radical includingits own substituent has a total length that is greater than a saturatedchain of five carbon atoms (a pentyl group), and preferably has a lengthgreater than that of a saturated chain of six carbon atoms (a hexylgroup); i.e., a length of about a heptyl chain or longer. An R³ radicalalso has a length that is less than that of a saturated chain of about20 carbon atoms [an icosyl group (icosyl was formerly spelled eicosyl)]and more preferably about 18 carbon atoms (a stearyl group). Mostpreferably, the length of R³ is about that of an 8 to about 12 carbonatom chain, even though many more atoms may be present in ringstructures or substituents. This length requirement is discussed furtherbelow.

Looked at more generally, and aside from specific moieties from which itis constructed, an R³ radical (group or moiety) has a length that isgreater than that of a pentyl group. Such an R³ radical also has alength that is less than that of an icosyl (didecyl) group. That is tosay that R³ is a radical having a minimal length longer that a saturatedfive carbon chain, and preferably greater than a hexyl group, but isshorter than the length of a saturated twenty carbon atom chain, andpreferably shorter than an eighteen carbon chain. Most preferably, R³has a length greater than that of an octyl group and less than that of alauryl group.

More specifically, an R³ group has a minimal length of a hexyl grouponly when that substituent is comprised of two rings that can be fusedor simply covalently linked together by exocyclic bonding. When R³ doesnot contain two linked or fused rings, e.g., where a R³ radical includesan alkyl or second, third or fourth ring substituent, R³ has a lengththat is greater than that of a hexyl group. Exemplary of such two ringR³ groups are a 2-naphthyl group or a 2-quinolinyl group (each with asix carbon chain length)and 8-purinyl (with a five carbon atom chainlength). Without wishing to be bound by theory, it is believed that thepresence of multiple rings in R³ enhances selectivity of the enzymeactivity inhibitor profile.

The radical chain lengths are measured along the longest linear atomchain in the radical, following the skeletal atoms around a ring wherenecessary. Each atom in the chain, e.g. carbon, oxygen, sulfur ornitrogen, is presumed to be carbon for ease in calculation.

Such lengths can be readily determined by using published bond angles,bond lengths and atomic radii, as needed, to draw and measure a desired,usually staggered, chain, or by building models using commerciallyavailable kits whose bond angles, lengths and atomic radii are in accordwith accepted, published values. Radical (substituent) lengths can alsobe determined somewhat less exactly by assuming that all atoms have bondlengths saturated carbon, that unsaturated bonds have the same lengthsas saturated bonds and that bond angles for unsaturated bonds are thesame as those for saturated bonds, although the above-mentioned modes ofmeasurement are preferred. For example, a phenyl or pyridyl group has alength of a four carbon chain, as does a propoxy group, whereas abiphenyl group has a length of about an eight carbon chain using such ameasurement mode.

In addition, a R³ group when rotated about an axis drawn through theSO₂-bonded 1-position and the 4-position of a 6-membered ring or theSO₂-bonded position and substituent-bonded 3- or 4-position of a5-membered ring defines a three-dimensional volume whose widestdimension has the width of about one furanyl ring to about two phenylrings in a direction transverse to that axis to rotation.

Thus, a 2-naphthyl substituent or an 8-purinyl substituent is anappropriately sized R³ group when examined using the above rotationalwidth criterion as well as the before-discussed criterion. On the otherhand, a i-naphthyl group or a 7- or 9-purinyl group is too wide uponrotation and is excluded from being an R³ group.

As a consequence of these length and width requirements, R³ radicalssuch as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl,4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl],4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl,4-[(4′-trifluoromethylthio)thiophenyl]phenyl,4-[(4′-trifluoromethyl)phenoxy]phenyl,4-[(4′-trifluoromethyl)thiophenyl]phenyl,4-[(4′-trifluoromethoxy)phenoxy]phenyl,4-[(4′-trifluoromethoxy)thiophenyl]phenyl,4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and4-(benzamido)phenyl are particularly preferred R³ radicals. Thosesubstituents can themselves also be substituted in the second ring fromthe SO₂ group at the meta- or para-position or both with a single atomor a substituent containing a longest chain length that is preferably ofup to five atoms, excluding hydrogen.

Without wishing to be bound by theory, the length of a R³ radicalsubstituent bonded to the SO₂ group is believed to play a role in theoverall activity of a contemplated inhibitor compound against MMPenzymes generally. The length of the R³ radical group also appears toplay a role in the selective activity of an inhibitor compound againstparticular MMP enzymes.

In particularly preferred practice, R³ is a PhR²³ group, wherein Ph isphenyl. The phenyl ring (Ph) of a PhR²³ group is substituted at itspara-position (4-position) by an R²³ group that can be anothersingle-ringed aryl or heteroaryl group, a piperidyl group, a piperazinylgroup, a phenoxy group, a thiophenoxy [C₆H₅—S—] group, a phenylazo[C₆H₅—N₂-] group or a benzamido [—NHC(O)C₆H₅] group.

In one embodiment of a particularly preferred aromatic sulfonehydroxamate inhibitor compound, an R²³ substituent is phenoxy and isitself substituted at its own para-position with a moiety that isselected from the group consisting of a halogen, a C₁-C₄ alkoxy group, aC₁-C₄ alkyl group, a dimethylamino group, a carboxyl C₁-C₃ alkylenegroup, a C₁-C₄ alkoxy carbonyl C₁-C₃ alkylene group, atrifluoromethylthio group, a trifluoromethoxy group, a trifluoromethylgroup and a carboxamido C₁-C₃ alkylene group, or is substituted at themeta- and para-positions by a methylenedioxy group. It is to beunderstood that any R²³ substituent can be substituted with a moietyfrom the above list. Such substitution at the para-position ispreferred.

The present invention also contemplates an intermediate compound that isuseful in preparing a compound of formulas I-V. Such an intermediatecompound corresponds in structure to formula VI, below:

wherein g is zero, 1 or 2;

R²⁰ is (a) —O—R²¹, where R²¹ is selected from the group consisting of ahydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceuticallyacceptable cation, or (b) —NH—O—R²² wherein R²² is a selectivelyremovable protecting group such as a 2-tetrahydropyranyl, C₁-C₆-acyl,aroyl, benzyl, p-methoxybenzyl (MOZ) carbonyl-C₁-C₆-alkoxy,trisubstituted silyl group or o-nitrophenyl group, peptide synthesisresin and the like, wherein trisubstituted silyl group is substitutedwith C₁-C₆-alkyl, aryl, or ar-C₁-C₆-alkyl;

-   -   m is zero, 1 or 2;    -   n is zero, 1 or 2;    -   p is zero, 1 or 2;    -   the sum of m+n+p=1, 2, 3 or 4;    -   (a) one of X, Y and Z is selected from the group consisting of        C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two        of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹, or    -   (b) X and Z or Z and Y together constitute a moiety that is        selected from the group consisting of NR⁶C(O), NR⁶S(O),        NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining        one of X, Y and Z being CR⁸R⁹, or    -   (c) n is zero and X, Y and Z together constitute a moiety        selected from the group consisting of        wherein wavy lines are bonds to the atoms of the depicted ring;    -   R⁶ and R^(6′) are independently selected from the group        consisting of hydrido, C₁-C₆-alkanoyl, C₆-aryl-C₁-C₆-alkyl,        aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)—C₁-C₆-alkyl, C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl,        C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl,        C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, C₆-aryl,        C₅-C₆-heterocyclo, C₅-C₆-heteroaryl,        C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₆-aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,        heteroarylthio-C₁-C₆-alkyl, C₆-arylsulfonyl,        C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl,        carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl,        aminocarbonyl, C₁-C₆-alkyliminocarbonyl, C₆-aryliminocarbonyl,        C₅-C₆-heterocycloiminocarbonyl, C₆-arylthio-C₁-C₆-alkyl,        C₁-₆-alkylthio-C₁-C₆-alkyl, C₆-arylthio-C₃-C₆-alkenyl,        C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl,        halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl,        thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl,        NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, an aminocarbonyl        wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl,        C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group,        hydroxyaminocarbonyl, an aminosulfonyl group wherein the        aminosulfonyl nitrogen is (i) unsubstituted or (ii) substituted        with one or two radicals independently selected from the group        consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and        a C₁-C₆-alkanoyl group, an amino-C₁-C₆-alkylsulfonyl group        wherein the amino-C₁-C₆-alkylsulfonyl nitrogen is (i)        unsubstituted or (ii) substituted with one or two radicals        independently selected from the group consisting of C₁-C₆-alkyl,        ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a C₁-C₆-alkanoyl group and        an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen        is (i) unsubstituted or (ii) substituted with one or two        radicals independently selected from the group consisting of        C₁-C₆-alkyl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl and a        C₁-C₆-alkanoyl group;    -   R⁷ is selected from the group consisting of a benzyl, phenyl,        C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group;    -   R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the        group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, aryl,        ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl,        C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl        cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,        hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl,        hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the        carbon to which they are bonded form a carbonyl group, or        wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with        the atoms to which they are bonded form a 5- to 8-membered        carbocyclic ring, or a 5- to 8-membered heterocyclic ring        containing one or two heteroatoms that are nitrogen, oxygen, or        sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and        R¹¹ is hydroxy;    -   R¹² and R^(12′) are independently selected from the group        consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl,        heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,        thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl,        heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,        aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl,        C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,        hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl,        aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl,        heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,        arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide        or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl,        trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group        wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii)        substituted with one or two radicals independently selected from        the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl        and C₁-C₆-alkanoyl;    -   R¹³ is selected from the group consisting of a hydrido, benzyl,        phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a        C₁-C₆-hydroxyalkyl group; and    -   R²⁴ is R³ as defined in formulas I, III, IV or is the        substituent G—A—R—E—Y of formula II (formula VIA).        Alternatively, R²⁴ is R^(3′), an aryl or heteroaryl group that        is substituted with a coupling substituent reactive for coupling        with another moiety (formula VIB), such as a nucleophilically        displaceable leaving group, D.        Exemplary nucleophilically displaceable leaving groups, D,        include a halo (fluoro, chloro, bromo, or idodo) nitro, azido,        phenylsulfoxido, aryloxy, C₁-C₆-alkoxy, a C₁-C₆-alkylsulfonate        or arylsulfonate group and a trisubstituted ammonium group in        which the three substituents are independently aryl,        ar-C₁-C₆-alkyl or C₁-C₆-alkyl. Additional coupling substituents        include, without limitation, a hydroxyl group and an amino group        that can be coupled with carbonyl-containing moieties to form        esters, urethanes, carbonates, amides and ureas. Similarly, a        carboxyl coupling substituent can be used to form an ester,        thioester or amide. Thus, a coupling substituent is useful in        converting a coupling substituent-containing aryl or heteroaryl        group into a substituent such as a G—A—R—E—Y substituent        discussed hereinabove by the formation of a covalent bond.

A compound of formula VI can be coupled with another moiety at theR^(3′) coupling substituent to form a compound whose newly formed R³group is that of formulas I, III, IV or —G —A—R—E—Y. Exemplary of suchcouplings are the nucleophilic displacement to form ethers andthioethers, as well as the formation of ester, amide, urea, carbonate,urethane and the like linkages.

A particularly preferred precursor intermediate to an intermediatecompound of formula VI is an intermediate compound of formula VII, below

wherein m, n, p, g, X, Z, Y, D and R²⁰ are as defined above for formulaVI.

-   -   R²⁰ is preferably —NH—O—R²², wherein R²² is a selectively        removable protecting group such as a 2-tetrahydropyranyl,        C₁-C₆-acyl, aroyl, benzyl, p-methoxybenzyl (MOZ)        carbonyl-C₁-C₆-alkoxy, o-nitrophenyl group, a peptide synthesis        resin such as a so-called Merrifield's Peptide Resin        commercially available from Sigma Chemical Co., and the like,        with 2-tetrahydropyranyl being particularly preferred. An        —NH—O—R²² group (R²⁰) in formulas VI and VII is therefore seen        to be a reaction product of a hydroxyl amine whose oxygen is        bonded to a selectively removable protecting group and a        carboxyl group.

In regard to a compound of each of formulas VI and VII, the subscriptletter age is used to show the oxidation state of the sulfur atom. Whereg is zero, the sulfur is unoxidized, and the compound depicted istypically the sulfide reaction product of a sulfur-containing synthon asis illustrated in the examples hereinafter. Where g is 1, the sulfur isoxidized to a sulfoxide, whereas when g is 2, the sulfur is oxidized toa sulfone as is also illustrated hereinafter. A compound of formulas VIor VII wherein g is zero or 1 are themselves typically intermediates inthe formation of a similar compound wherein g is 2 and the intermediateis a preferred sulfone.

A preferred intermediate therefore corresponds in structure to formulaVIIA, below

In the written descriptions of molecules and groups, moleculardescriptors can be combined to produce words or phrases that describestructural groups or are combined to describe structural groups. Suchdescriptors are used in this document. Common illustrative examplesinclude such terms as aralkyl (or arylalkyl), heteroaralkyl,heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like.A specific example of a compound encompassed with the latter descriptoraralkoxyalkoxycarbonyl is C₆H₅—CH₂—CH₂—O—CH₂—O—(C═O)— wherein C₆H₅— isphenyl. It is also to be noted that a structural group can have morethan one descriptive word or phrase in the art, for example,heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl.Such combinations are used herein in the description of the processes,compounds and compositions of this invention and further examples aredescribed below. The following list is not intended to be exhaustive ordrawn out but provide illustrative examples of words or phrases (terms)that are used herein.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing 1 to about 12carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably1 to about 6 carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl, octyl and the like.

The term “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds andcontaining 2 to about 12 carbon atoms preferably 2 to about 10 carbonatoms, and more preferably, 2 to about 6 carbon atoms. Examples ofsuitable alkenyl radicals include ethenyl (vinyl), 2-propenyl,3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl,3-butenyl, decenyl and the like.

The term “alkynyl”, alone or in combination, means a straight-chainhydrocarbon radical having one or more triple bonds and containing 2 toabout 12 carbon atoms, preferably 2 to about 10 carbon atoms, and morepreferably, 2 to about 6 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl,3-butynyl, and the like.

The term “carbonyl” or “oxo”, alone or in combination, means a —C(═O)—group wherein the remaining two bonds (valences) can be independentlysubstituted. The term carbonyl is also intended to encompass a hydratedcarbonyl group —C(OH)₂—.

The term “thiol” or “sulfhydryl”, alone or in combination, means a —SHgroup. The term “thiol” or “thia”, alone or in combination, means athiaether group; i.e., an ether group wherein the ether oxygen isreplaced by a sulfur atom.

The term “amino”, alone or in combination, means an amine or —NH₂ groupwhereas the term mono-substituted amino, alone or in combination, meansa substituted amine —N(H)(substituent) group wherein one hydrogen atomis replaced with a substituent, and disubstituted amine means a—N(substituent)₂ wherein two hydrogen atoms of the amino group arereplaced with independently selected substituent groups.

Amines, amino groups and amides are compounds that can be designated asprimary (I°), secondary (II°) or tertiary (III°) or unsubstituted,mono-substituted or N,N-disubstituted depending on the degree ofsubstitution of the amino nitrogen. Quaternary amine (ammonium) (IV°)means a nitrogen with four substituents [—N⁺(substituent)₄] that ispositively charged and accompanied by a counter ion, whereas N-oxidemeans one substituent is oxygen and the group is represented as[—N⁺(substituent)₃—O⁻]; i.e., the charges are internally compensated.

The term “cyano”, alone or in combination, means a —C-triple bond-N(—C≡N) group. The term “azido”, alone or in combination, means a—N-triple bond-N (—N≡N) group. The term “hydroxyl”, alone or incombination, means a —OH group. The term “nitro”, alone or incombination, means a —NO₂ group. The term “azo”, alone or incombination, means a —N═N— group wherein the bonds at the terminalpositions can be independently substituted.

The term “hydrazino”, alone or in combination, means a —NH—NH— groupwherein the depicted remaining two bonds (valences) can be independentlysubstituted. The hydrogen atoms of the hydrazino group can be replaced,independently, with substituents and the nitrogen atoms can form acidaddition salts or be quaternized.

The term “sulfonyl”, alone or in combination, means a —SO₂— groupwherein the depicted remaining two bonds (valences) can be independentlysubstituted. The term “sulfoxido”, alone or in combination, means a —SO—group wherein the remaining two bonds (valences) can be independentlysubstituted.

The term “sulfone”, alone or in combination, means a —SO₂— group whereinthe depicted remaining two bonds (valences) can be independentlysubstituted. The term “sulfenamide”, alone or in combination, means a—SON═ group wherein the remaining three depicted bonds (valences) can beindependently substituted. The term “sulfide”, alone or in combination,means a —S— group wherein the remaining two bonds (valences) can beindependently substituted.

The term “alkoxy”, alone or in combination, means an alkyl ether radicalwherein the term alkyl is as defined above. Examples of suitable alkylether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “cycloalkyl”, alone or in combination, means a cyclic alkylradical that contains 3 to about 8 carbon atoms. The term“cycloalkylalkyl” means an alkyl radical as defined above that issubstituted by a cycloalkyl radical containing 3 to about 8, preferably3 to about 6, carbon atoms. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

A heterocyclic (heterocyclo) or heterocyclo portion of aheterocyclocarbonyl, heterocyclooxycarbonyl, heterocycloalkoxycarbonyl,or heterocycloalkyl group or the like is a saturated or partiallyunsaturated monocyclic, bicyclic or tricyclic heterocycle that containsone or more hetero atoms selected from nitrogen, oxygen and sulphur.Such a moiety can be optionally substituted on one or more ring carbonatoms by halogen, alkyl, alkoxy, oxo, and the like, and/or on asecondary nitrogen atom (i.e., —NH—) of the ring by alkyl,aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogenatom (i.e., ═N—) by oxido and that is attached via a carbon atom. Thetertiary nitrogen atom with three substituents can also attached to forma N-oxide [═N(O)—] group.

The term “aryl”, alone or in combination, means a 5- or 6-memberedcarbocyclic aromatic ring-containing moiety or a fused ring systemcontaining two or three rings that have all carbon atoms in the ring;i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicalsinclude phenyl, indenyl and naphthyl radicals.

The term “heteroaryl”, alone or in combination means a 5- or 6-memberedaromatic ring-containing moiety or a fused ring system (radical)containing two or three rings that have carbon atoms and also one ormore heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen.Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl,piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl,imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, andthe like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl,tetrahydrofuryl, thienyl, triazolyl, oxazolyl, oxadiazoyl, thiazolyl,thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g.,2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like),isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like),tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and thelike), 1,2,3,4-tetrahydroisoquinolinyl (e.g.,1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or5-benzimidazolyl, and the like radicals.

When an aryl or heteroaryl radical is a substituting moiety (group,substituent, or radical), it can itself substituted, the last-namedsubstituent is independently selected from the group consisting of acyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl,trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo,alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio,aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio,heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio,heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy,heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo,heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy,alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy,hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl,aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl,arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

-   -   wherein the amino nitrogen is (i) unsubstituted, or (ii)        substituted with one or two substituents that are independently        selected from the group consisting of an alkyl, aryl,        heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl,        alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl,        heteroaralkanoyl and an alkanoyl group, or (iii) wherein the        amino nitrogen and two substituents attached thereto form a 5-        to 8-membered heterocyclo or heteroaryl ring containing zero to        two additional heteroatoms that are nitrogen, oxygen or sulfur        and which ring itself is (a) unsubstituted or (b) substituted        with one or two groups independently selected from the group        consisting of an aryl, alkyl, heteroaryl, aralkyl,        heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl,        heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl,        benzofused heterocycloalkyl, hydroxyalkoxyalkyl,        aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused        heterocycloalkoxy, benzofused cycloalkylcarbonyl,        heterocycloalkylcarbonyl, and a cycloalkylcarbonyl group,        carbonylamino    -   wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii)        is the reacted amine of an amino acid, or (iii) substituted with        one or two radicals selected from the group consisting of an        alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl,        trifluoromethylalkyl, heterocycloalkyl, benzofused        heterocycloalkyl, benzofused heterocycloalkyl, benzofused        cycloalkyl, and an N,N-dialkyl substituted alkylamino-alkyl        group, or (iv) the carboxamido nitrogen and two substituents        bonded thereto together form a 5- to 8-membered heterocyclo,        heteroaryl or benzofused heterocycloalkyl ring that is itself        unsubstituted or substituted with one or two radicals        independently selected from the group consisting of an alkyl,        alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy,        hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino        group,        -   wherein the amino nitrogen is (i) unsubstituted, or (ii)            substituted with one or two substituents that are            independently selected from the group consisting of alkyl,            aryl, and heteroaryl, or (iii) wherein the amino nitrogen            and two substituents attached thereto form a 5- to            8-membered heterocyclo or heteroaryl ring,            and an aminoalkyl group    -   wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii)        substituted with one or two substituents independently selected        from the group consisting of an alkyl, aryl, aralkyl,        cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl        group, or (iii) wherein the aminoalkyl nitrogen and two        substituents attached thereto form a 5- to 8-membered        heterocyclo or heteroaryl ring.

The term “aralkyl”, alone or in combination, means an alkyl radical asdefined above in which one hydrogen atom is replaced by an aryl radicalas defined above, such as benzyl, 2-phenylethyl and the like.

The term “aralkoxycarbonyl”, alone or in combination, means a radical ofthe formula aralkyl-O—C(O)— in which the term “aralkyl” has thesignificance given above. An example of an aralkoxycarbonyl radical isbenzyloxycarbonyl.

The term “aryloxy” means a radical of the formula aryl-O— in which theterm aryl has the significance given above. The phenoxy radical is anexemplary aryloxy radical.

The terms “heteroaralkyl” and “heteroaryloxy” mean radicals structurallysimilar Lo aralkyl and aryloxy that are formed from heteroaryl radicals.Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.

The terms “alkanoyl” or “alkylcarbonyl”, alone or in combination, meansan acyl radical derived from an alkanecarboxylic acid, examples of whichinclude formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl,and the like.

The term “cycloalkylcarbonyl” means an acyl group derived from amonocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid that isoptionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.

The terms “aralkanoyl” or “aralkylcarbonyl” mean an acyl radical derivedfrom an aryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyland the like.

The terms “aroyl” or “arylcarbonyl” means an acyl radical derived froman aromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “cycloalkylalkoxycarbonyl” means an acyl group of the formulacycloalkylalkyl-O—CO— wherein cycloalkylalkyl has the significance givenabove. The term “aryloxyalkanoyl” means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the significance givenabove. The term “heterocyclooxycarbonyl” means an acyl group having theformula heterocyclo-O—CO— wherein heterocyclo is as defined above.

The term “heterocycloalkanoyl” is an acyl radical of the formulaheterocyclo-substituted alkane carboxylic acid wherein heterocyclo hasthe significance given above. The term “heterocycloalkoxycarbonyl” meansan acyl radical of the formula heterocyclo-substituted alkane-O—CO—wherein heterocyclo has the significance given above.

The term “heteroaryloxycarbonyl” means an acyl radical represented bythe formula heteroaryl-O—CO— wherein heteroaryl has the significancegiven above.

The term “aminocarbonyl” (carboxamide) alone or in combination, means anamino-substituted carbonyl (carbamoyl) group derived from an aminereacted with a carboxylic acid wherein the amino (amido nitrogen) groupis unsubstituted (—NH₂) or a substituted primary or secondary aminogroup containing one or two substituents selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like, as recited. A hydroxamate is aN-hydroxycarboxamide.

The term “aminoalkanoyl” means an acyl group derived from anamino-substituted alkanecarboxylic acid wherein the amino group can be aprimary or secondary amino group containing substituents independentlyselected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like.

The term “halogen” means fluoride, chloride, bromide or iodide. The term“haloalkyl” means an alkyl radical having the significance as definedabove wherein one or more hydrogens are replaced with a halogen.Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl andthe like.

The term “perfluoroalkyl” means an alkyl group wherein each hydrogen hasbeen replaced by a fluorine atom. Examples of such perfluoroalkylgroups, in addition to trifluoromethyl above, are perfluorobutyl,perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

The term “perfluoroalkoxy” alone or in combination, means aperfluoroalkyl ether radical wherein the term perfluoroalkyl is asdefined above. Examples of such perfluoroalkoxy groups, in addition totrifluoromethoxy (F₃C—O—), are perfluorobutoxy, perfluoroisopropoxy,perfluorododecoxy and perfluorodecoxy.

The term “perfluoroalkylthio” alone or in combination, means aperfluoroalkyl thioether radical wherein the term perfluoroalkyl is asdefined above. Examples of such perfluoroalkylthio groups, in additionto trifluoromethylthio (F₃C—S—), are perfluorobutylthio,perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.

The term “aromatic ring” in combinations such as substituted-aromaticring sulfone or substituted-aromatic ring sulfoxide means aryl orheteroaryl as defined before.

The term “pharmaceutically acceptable” is used adjectivally herein tomean that the modified noun is appropriate for use in a pharmaceuticalproduct. Pharmaceutically acceptable cations include metallic ions andorganic ions. More preferred metallic ions include, but are not limitedto appropriate alkali metal (Group Ia) salts, alkaline earth metal(Group IIa) salts and other physiological acceptable metal ions.Exemplary ions include aluminum, calcium, lithium, magnesium, potassium.sodium and zinc in their usual valences. Preferred organic ions includeprotonated tertiary amines and quaternary ammonium cations, including inpart, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Exemplary pharmaceutically acceptableacids include without limitation hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid,formic acid, tartaric acid, maleic acid, malic acid, citric acid,isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronicacid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid,aspartic acid, glutamic acid, benzoic acid, and the like.

“M” utilized in the reaction schemes that follow represents a leavinggroup such as halogen, phosphate ester or sulfate ester.

Preparation of Useful Compounds

Schemes A through C and Schemes 1 through 19 hereinbelow illustratechemical processes and transformations that can be useful for thepreparation of compounds useful in this invention; i.e., compounds offormulas I, II, III, IV and V and similar cyclic inhibitors. Inaddition, the preparation of compounds of formula VI and formula VII isillustrated. Compounds of formula VI and formula VII can be used asintermediates in the preparation of the compounds of formulas I, II,III, IV and V or pro-drugs or MMP inhibitors.

In Schemes A through C, the symbol J independently represents R²⁰ orother synthetically useful groups such as amides, acid chlorides, mixedanhydrides and the like. The n is 0, 1 or 2 and is preferred to be 1 or2 in Scheme C. The n of these schemes corresponds to g in formulas VIand VII, and is zero, 1 or 2. The symbol m is 1 or 2. The symbol r isindependently 1, 2 or 3. The symbol P represents a protecting group thatcan also be a member of the group R⁶. In Scheme A, for simplicity andclarity of illustration positional isomers are illustrated with a bondthrough the ring in standard fashion. Later Schemes typically only showone positional isomer but positional isomers are represented by thesestructures and reactions in a manner consistent with Formula I, II, III,IV, V, VI, VII above. Similarly, the symbol B represents O, S, SO, SO₂and NR⁶. The symbols C and C′ independently are electrophilic groups orgroups capable of participating in a condensation reaction. Here to itshould be noted that the six-membered ring is shown for illustrativepurposes but the procedures and/or reagents are applicable to andrepresent combinations the permit the preparation of 5- to 8-memberedrings.

The structures in Schemes 1 through 19 are also shown with compoundsthat represent the other compounds of this invention. The aromatic ringin Scheme C is aryl and heteroaryl. The moieties of —A—R—E—Y are asdefined before. Reactions illustrated involving a spiroheterocyclicnitrogen atom may not be applicable to those compounds with sulfur oroxygen.

Scheme A shows in step 1 the reduction of a heteraryl compound to acarboxyl derivative. Generally, the first product is ahydrogen-containing amine heterocycle when the starting material isaromatic or an R⁶-containing heterocycle when a partially unsaturatedheterocycle is the starting material.

Compound 2 can be treated in several ways depending on the needs of thechemist. In Step 2, the nitrogen can be protected by preparing, forexample, a carbobenzoxy (Z) or tert-butoxycarbonyl derivative. Suchacylations can be carried out by methods well known in the art,especially the art of amino acid and peptide synthesis. The process ofacylation with activated carboxyl group- or activated sulfonylgroup-containing reagents to prepare contemplated compounds is carriedout in the same manner. Examples of such acylating groups are carbonylazides, halides, anhydrides, mixed anhydrides, carbodiimide derivativesor other less traditional activated ester groups such as thehydroxybenzotriazole derivative. These acylations can be run in thepresence of base including mild bases such as triethylamine orN-ethylmorpholine if desired. The preparation of some activated esterreagents and their use to prepare other compounds useful in thisinvention is discussed below. It should be recalled that the groupsconstituting P and serving as a selectively removable protecting groupcan also be included as part of the group R⁶.

Step 4 of Scheme A shows the alkylation or acylation of Compound 2 toproduce compound 5. The process of acylation and alkylation are asdiscussed herein. In Step 5, the group J can be changed if desired. Anexample of such a change is exchange of an ester for a THP-protectedhydroxamate conversion of a THP-protected hydroxamate into a hydroxamateor conversion of an acid into a protected hydroxamate or the like.

Steps 3, 7 and 8 show the preparation of sulfur-containing derivativesof the contemplated compounds or intermediates to those compounds. Thestarting material for the above steps (e.g., compounds 2, 5 and 6) canbe treated with a base to deprotonate the carbon alpha to the carbonylfunction. This anion can be reacted with a sulfur electrophile toproduce a sulfone, sulfoxide or sulfide. Such electrophiles can be ofthe form of, for example, R²⁴S—SR²⁴, R²⁴SO₂C₁, R²⁴SC₁, R²⁴SOC₁,R²⁴S(O)—SR₂₄ and the like where R²⁴ is as defined before or is an arylor heteroaryl sulfur-containing material containing a couplingsubstituent, R^(3′), that can be used to prepare one of theR²⁴-containing groups. Preparation of the anion requires a base and astrong base may be required such as one of the metal amides, hydrides oralkyls discussed herein. The solvents are nonprotic, and dipolar aproticsolvents are preferred along with an inert atmosphere. Subsequentschemes usually utilize R³ for the R²⁴ group for ease of illustration.

It should be noted that these processes produce sulfides (thio ethers),sulfoxides or sulfones depending on starting material. In addition, thesulfides can be oxidized to sulfoxides or sulfones, and the sulfoxidescan be oxidized to their corresponding sulfone derivatives. The choiceof position in the synthetic sequence to change the oxidation state ofsulfur as well as the decision to change oxidation state is under thecontrol of the chemist skilled in the art. Methods of oxidizing sulfurare discussed hereinbelow.

Scheme A, Steps 6, 9, 10 and 12 independently illustrate theinterconversion of groups within J. Examples of such interconversionsinclude exchange of an ester for hydroxamic acid or hydroxamic acidderivative, conversion of a carboxylic acid into an activated carbonylderivative or into a hydroxamic acid or hydroxamic acid derivative(pro-drug or protected derivative), or removal of a protecting groupfrom a hydroxamate derivative. The preparation of activated carbonylcompounds their reaction with nucleophiles such as hydroxamic acid,protected hydroxamates or hydroxamic acid pro-drugs is discussed belowas is the conversion of protected hydroxamic acid derivatives intohydroxamic acids. The preparation of, for example,hydroxybenzotriazole/carbodiimide, derived products is discussed herein.The preparation or hydrolysis of esters, amides, amide derivatives, acidchlorides, acid anhydrides, mixed anhydrides and the like are syntheticmethods very well known in the art, and are not discussed in detailherein. Step 6 illustrates the conversion of compound 4 into compound 9,without first being converted into compound 7.

Scheme B illustrates an alternate method of preparing contemplatedcompounds. The reagent shown above the arrow in Step 1 is a reagent withtwo active groups in addition to the heteroatoms (B) noted before. Hereagain, the particular reagent illustrated was selected to permit a clearillustration of the reaction, but it is also intended to representreagents that permit the preparation of the heteroatom position, and 5-,7- and 8-membered ring size compounds. These reagents are readilyselected by those skilled in the art.

C and C′ in this Step 1 reagent are independently an electophile or agroup convertible into an electrophile. Such groups include halides,sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups, and thelike. This reagent is reacted with a nucleophilic anion of a sulfurcontaining carbonyl compound such as compound 1. The anion is formed bydeprotonation of compound 1 and examples of bases suitable for such adeprotonation are discussed below. Treatment with the aboveelectrophilic reagent is carried out under alkylating conditions wellknown in the art and discussed herein. The product of this reaction canbe either Compound 2 or Compound 3; i.e., the reaction can be carriedout as a pot or two step process as required.

Step 3 illustrates the interconversion of J groups if desired asdiscussed above for Scheme A. Step 4 uses reagent where C, for example,represents a nucleophile as discussed above and C′ represents anelectrophile or a nucleophile such as hydroxyl, thiol or R⁶-amino. It isnoted that C′ can be, independently, a nucleophile or an electrophilewhen m is 2; i.e., the C′ groups are not required to be the same when mis 2. When m is 2, treatment with a second mole of base provides theskilled chemist an alternative preparation of Compound 5. When C′ ishydroxyl, thiol, or R⁶-amino and m is 2, the person skilled in the artcan condense Compound 4 with, for example, an aldehyde or ketone, underreductive conditions or with subsequent reduction to form a contemplatedcompound. As above, the compound where m is 2 can be made in one step(one pot process) or two steps, thus permitting the chemist the choiceof having the reagent(s) be the same (one pot) or different (two step).

Scheme B also illustrates the interconversions of the groups within J,the oxidation state of the sulfur and groups on nitrogen; i.e., R⁶groups, to provide the contemplated compounds. These methods andprocesses are discussed above for the reactions of Scheme A.

Scheme C illustrates the nucleophilic displacement of a group D asdefined herein. This reaction is carried out in a similar manner to thedisplacement reactions discussed herein. The choice of oxidation stateof the sulfur is made by the person skilled in the art, but sulfoxide orsulfone groups are preferred, and the sulfone is most preferred. Thedisplacement can be carried out either before or after the methylenenext to the carbonyl group is reacted to form a spiro heterocyclicgroup.

Steps 1, 2 and 3 also illustrate that although the nucleophilicdisplacement can be carried out with one nucleophile (Nu), the productof this reaction can be modified by methods well known in the art and asshown herein to provide the group —A—R—E—Y as defined hereinbefore.

A non-limiting illustration of such a process is provided when D isfluoride. The fluoride leaving group can be directly displaced with theanion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol,4-trifluoromethylthiophenol and the like to provide a contemplatedcompound. This is a one pot process from Compound 4. Other compoundsincluded in —A—R—E—Y can be prepared by displacing the fluoride leavinggroup with ammonia to provide an amine, which can then be acylated bymethods discussed wherein with, for example, 4-trifluoromethylbenzoylchloride, to form another contemplated product compound.

The R⁶ function can be changed and/or further modified in compounds orat steps in the Schemes as desired or required by the person skilled inthe art to prepare the contemplated compounds. Interconversion of dualpurpose functional groups such as short or long term protecting groupsinto other R⁶ groups has been mentioned. Many other routine and/oruseful conversions, including the preparation of syntheticintermediates, are very well known in the art. A few non-limitingexamples of such conversions or reactions include: reductions;nucleophilic displacement/substitution reactions; exchange orpreparation of carboxylic or sulfonic acids, amides, esters, acidhalides, mixed anhydrides and the like; electrophilicdisplacement/substitution reactions; oxidations; ring/chain conversions,ring opening reactions, condensation reactions including those involvingsulfonyl or carbonyl groups and/or carbon-hydrogen bonds influenced byeither or both of those groups. The selection of preparative methods orconversion methods of the contemplated compounds and the order of thereaction(s) is made by the skilled person. It is expected that should aparticular sequence or method prove to be undesirable that analternative will be selected and used. Included is the choice ofpreparing/adding the groups in a single step using a convergentinhibitor strategy or preparing the final R⁶ group following a stepwisestrategy.

Thus, in general, the choices of starting material and reactionconditions can vary as is well known to those skilled in the art.Usually, no single set of conditions is limiting because variations canbe applied as required. Conditions are also selected as desired to suita specific purpose such as small scale preparations or large scalepreparations. In either case, the use of less safe or lessenvironmentally sound materials or reagents is usually be minimized.Examples of such materials are diazomethane, diethyl ether, heavy metalsalts, dimethyl sulfide, chloroform, benzene and the like.

These reactions can be carried out under a dry inert atmosphere such anitrogen or argon if desired. Selected reactions known to those skilledin the art, can be carried out under a dry atmosphere such as dry airwhereas other synthetic steps, for example, aqueous acid or base esteror amide hydrolysis, can be carried out under laboratory air. Inaddition, some processes of these syntheses can be carried out in apressure apparatus at pressures above, equal to or below atmosphericpressure. The use of such an apparatus aids in the control of gaseousreagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygenand the like, and can also help prevent the leakage of air or humidityinto a reaction in progress. This discussion is not intended to beexhaustive as it is readily noted that additional or alternativemethods, conditions, reactions or systems can be identified and used bya chemist of ordinary skill.

The illustrated reactions are usually carried out at a temperature ofbetween −25° C. to solvent reflux under an inert atmosphere such asnitrogen or argon. The solvent or solvent mixture can vary widelydepending upon reagents and other conditions and can include polar ordipolar aprotic solvents as listed or mixtures of these solvents.Reactions can be carried out at lower temperatures such as dryice/acetone or liquid nitrogen temperature if desired to carry out suchreactions as metalations or anion formations using strong bases.

In some cases, amines such as triethylamine, pyridine or othernon-reactive bases can serve as reagents and/or solvents and/orco-solvents. In some instances, in these reactions and other reactionsin these Schemes, protecting groups can be used to maintain or retaingroups in other parts of a moleculets) at locations that is(are) notdesired reactive centers. Examples of such groups that the skilledperson can maintain or retain include, amines, other hydroxyls, thiols,acids and the like. Such protecting groups can include acyl groups,arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers,cycloalkyloxy ethers, arylalkyl groups, silyl groups includingtrisubstituted silyl groups, ester groups and the like. Examples of suchprotecting groups include acetyl, trifluoroacetyl, tetrahydropyran(THP), benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Zor CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM)groups. The preparation of such protected compounds as well as theirremoval is well known in the art. The protecting groups can also be usedas substituents in the contemplated compounds whose utility is as a drugrather than as a synthetic intermediate.

Many reactions or processes involve bases that can act as reactants,reagents, deprotonating agents, acid scavengers, salt forming reagents,solvents, co-solvents and the like. Bases that can be used include, forexample, metal hydroxides such as sodium, potassium, lithium, cesium ormagnesium hydroxide, oxides such as those of sodium, potassium, lithium,calcium or magnesium, metal carbonates such as those of sodium,potassium, lithium, cesium, calcium or magnesium, metal bicarbonatessuch as sodium bicarbonate or potassium bicarbonate, primary (I°),secondary (II°) or tertiary (III°) organic amines such as alkyl amines,arylalkyl amines, alkylarylalkyl amines, heterocyclic amines orheteroaryl amines, ammonium hydroxides or quaternary ammoniumhydroxides. As non-limiting examples, such amines can includetriethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine,diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine,N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine,1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine, and the like. Non-limitingexamples of ammonium hydroxides, usually made from amines and water, caninclude ammonium hydroxide, triethylammonium hydroxide,trimethylammonium hydroxide, methyldiiospropylammonium hydroxide,tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide,morpholinium hydroxide, N-methylmorpholinium hydroxide,N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, andthe like. As non-limiting examples, quaternary ammonium hydroxides caninclude tetraethylammonium hydroxide, tetramethylammonium hydroxide,dimethyldiiospropyl-ammonium hydroxide, benzylmethyldiisopropylammoniumhydroxide, methyldiazabicyclononylammonium hydroxide,methyltribenzylammonium hydroxide, N,N-dimethylmorpholiniumhydroxide,N,N,N′,N′-tetramethylpiperazinium hydroxide, andN-ethyl-N′-hexylpiperidinium hydroxide and the like.

Metal hydrides, amides or alcoholates such as calcium hydride, sodiumhydride, potassium hydride, lithium hydride, aluminum hydride,diisobutylaluminum hydride (DIBAL) sodium methoxide, potassiumtert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide,potassium diisopropyl amide and the like can also be suitable reagents.Organometallic deprotonating agents such as alkyl or aryl lithiumreagents such as methyl lithium, phenyl lithium, tert-butyl lithium,lithium acetylide or butyl lithium, Grignard reagents such asmethylmagnesium bromide or methymagnesium chloride, organocadmiumreagents such as dimethylcadmium and the like can also serve as basesfor causing salt formation or catalyzing the reaction. Quaternaryammonium hydroxides or mixed salts are also useful for aiding phasetransfer couplings or serving as phase transfer reagents.Pharmaceutically acceptable bases can be reacted with acids to formcontemplated pharmaceutically acceptable salts. It should also be notedthat optically active bases can be used to make optically active saltswhich can be used for optical resolutions.

Generally, reaction media can comprise a single solvent, mixed solventsof the same or different classes or serve as a reagent in a single ormixed solvent system. The solvents can be protic, non-protic or dipolaraprotic. Non-limiting examples of protic solvents include water,methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanoland the like. Typical non-protic solvents include acetone,tetrahydrofuran (THF), dioxane, diethyl ether, tert-butylmethyl ether(TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate,methyl acetate, butyl acetate, trichloroethane, methylene chloride,ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane andthe like. Dipolar aprotic solvents include compounds such asdimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO,hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea,N-methylpyrrolidone and the like. Non-limiting examples of reagents thatcan be used as solvents or as part of a mixed solvent system includeorganic or inorganic mono- or multi-protic acids or bases such ashydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formicacid, citric acid, succinic acid, triethylamine, morpholine,N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine,potassium hydroxide, sodium hydroxide, alcohols or amines for makingesters or amides or thiols for making contemplated products and thelike.

The preparation of compounds contemplated herein can require theoxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides orsulfones. Reagents for this process can include, in a non-limitingexample, peroxymonosulfate (OXONE®), hydrogen peroxide,meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlacticacid, tert-butyl peroxide, tert-butyl hypochlorite, sodiumhydpochlorite, hypochlorous acid, sodium meta-periodate, periodic acidand the like with the weaker agents being most useful for thepreparation of sulfones and sulfoxides. Protic, non-protic, dipolaraprotic solvents, either pure or mixed, can be chosen, for example,methanol/water.

The oxidation can be carried out at temperature of about −78° to about50° degrees Centigrade, and normally selected from a range −10° C. toabout 40° C. Sulfoxides are best prepared using one equivalent ofoxidizing agent. It can be desirable in the case of more activeoxidizing agents, but not required, that the reactions be carried outunder an inert gas atmosphere with or without degassed solvents. Itshould be noted that the oxidation of sulfides to sulfones can becarried out in one step or two steps via the sulfoxide as desired by thechemist.

Reduction is a well known process in the art with a useful method beinghydrogenation. In such cases (catalytic reduction), there can be a metalcatalyst such as Rh, Pd, Pt, Ni or the like with or without anadditional support such as carbon, barium carbonate and the like.Solvents can be protic or non-protic pure solvents or mixed solvents asrequired. The reductions can be carried out at atmospheric pressure to apressure of multiple atmospheres with atmospheric pressure to about 40pounds per square inch (psi) preferred or very high pressures in specialhydrogenation equipment well known in the art.

Reductive alkylation of amines or active methylene compounds is also auseful method of preparing compounds. Such alkylations can be carriedout under reductive hydrogenation conditions as presented above using,for example, aldehydes or ketones. Hydride transfer reagents such assodium cyanoborohydride, aluminum hydride, lithium aluminumhydride,borane, sodium borohydride, diisobutylaluminum hydride and the like arealso useful as reagents for reductive alkylation. Acyl groups can bereduced in a similar manner to produce substituted amines.

Alternative methods of alkylating carbon or nitrogen are directalkylation. Such an alkylation, as is well known in the art, can becarried by treatment of an activated carbon containing at least onehydrogen with base to form the corresponding anion, adding anelectrophilic reagent and permitting the SN2 reaction to proceed. Anamine to be alkylated is treated similarly except that deprotonation maynot be required. Electrophiles include halogen derivatives, sulfonateesters, epoxides and the like.

Bases and solvents for alkylation reactions are those discussed above.Preferred are bases that are hindered such that competition with theelectrophile is minimized. Additional preferred bases are metalhydrides, amide anions or organometallic bases such as n-butyl lithium.The solvents, solvent mixtures or solvent/reagent mixtures discussed aresatisfactory but non-protic or dipolar aprotic solvents such as acetone,acetonitrile, DMF and the like are examples of preferred classes.

Acids are used in many reactions during various syntheses. For example,removal of the THP protecting group to produce the hydroxamic acid. Theacid can be a mono-, di- or tri-protic organic or inorganic acid.Examples of acids include hydrochloric acid, phosphoric acid, sulfuricacid, acetic acid, formic acid, citric acid, succinic acid, hydrobromicacid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluenesulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid,difluoroacetic acid, benzoic acid, methane sulfonic acid, benzenesulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid,nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and thelike. They can also be Lewis acids such as aluminum chloride,borontrifluoride, antimony pentafluoride and the like. Acids in a proticcan also be used to hydrolyze esters, amides and the like as well ascatalyze exchange reactions.

Conversion of a carboxylic acid protected as an ester or amide into ahydroxamic acid or hydroxamic acid derivative such as anO-arylalkylether or O-cycloalkoxyalkylether group is useful. In the casewhere hydroxylamine is used, treatment of an ester or amide with one ormore equivalents of hydroxylamine hydrochloride at room temperature orabove in a solvent or solvents, usually protic or partially protic, suchas those listed above can provide a hydroxamic acid directly. Thisexchange process can be further catalyzed by the addition of additionalacid. Alternatively, a base such as a salt of an alcohol used as asolvent, for example, sodium methoxide in methanol, can be used to formhydroxylamine from hydroxylamine hydrochloride in situ which canexchange with an ester or amide. As mentioned above, exchange can becarried out with a protected hydroxyl amine such astetrahydropyranylhydroxyamine (THPONH₂), benzylhydroxylamine (BnONH₂),and the like in which case compounds such as shown in Schemes A, B and Cthat are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acidderivatives are the products. Removal of the protecting groups whendesired, for example, following further transformations in another partof the molecule or following storage, is accomplished by standardmethods well known in the art such as acid hydrolysis of the THP groupas discussed above or reductive removal of the benzyl group withhydrogen and a metal catalyst such as palladium, platinum, palladium oncarbon or nickel.

In the case where R²⁰ is hydroxyl; i.e., where the intermediate is acarboxylic acid, standard coupling reactions can be used. For example,the acid can be converted into an acid chloride, mixed anhydride oractivated ester such as hydroxybenzotriazole and treated withhydroxylamine or a protected hydroxylamine in the presence of anon-competitive base to the nitrogen acylated compound. This is the sameproduct as discussed above. Couplings of this nature are well known inthe art and especially the art related to peptide and amino acidchemistry.

Compounds contemplated herein can possess one or more asymmetric carbonatoms and are thus capable of existing in the form of optical isomers,enantiomers, diastereoisomers, as well as in the form of racemic ornonracemic mixtures. A compound can also exist in other isomeric formssuch as ortho, meta and para isomers, cis and trans isomers, syn andanti isomers, E and Z isomers, tautomeric isomers, alpha and betaisomers, axial and equatorial isomers and isomers due to hinderedrotation. An isomer can exist in equilibrium with another isomer in amammal or a test system. Such a compound can also exist as an isomericequilibrium system with a solvent or water, for example, as a hydratedketone or aldehyde, as is well known in the art. All isomers areincluded as compounds of this invention.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, are applicable to thepreparation of the corresponding compounds that are contemplated.

Table 1 through Table 150, below, show several contemplated aromaticsulfone hydroxamic acid inhibitor compounds or structural formulas thatillustrate substituent groups. Each group of compounds is illustrated bya generic formula, or formulae, followed by a series of preferredmoieties or groups that constitute various substituents that can beattached at the position clearly shown in the generic structure. Thesubstituent symbols, e.g., R1 and R2 and R3, are as shown in each Table,and are typically not those used before. One or two bonds (wavy lines)are shown with those substituents to indicate the respective positionsof attachment in the illustrated compound. This system is well known inthe chemical communication arts and is widely used in scientific papersand presentations. For example in Table 2, R1 and R2 together with theatoms to which they are bonded is the variable group with the structuralentities that can substitute for R1 and R2 together shown in the balanceof that table.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

TABLE 2 II

1

2

3

4

5

6

7

8

9

10

11

12

TABLE 3

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 5

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 6

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 7

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 8

1

2

3

4

5

6

7

8

9

10

11

TABLE 9

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 10

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 11

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 12

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 13

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 14

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 15

1

2

3

4

5

6

7

8

9

10

11

TABLE 16

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 17

1

2

3

4

5

6

7

8

9

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15

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17

18

TABLE 18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 19

1

2

3

4

5

6

7

8

9

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11

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13

14

15

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17

18

19

20

21

22

TABLE 20

1

2

3

4

5

6

7

8

9

10

11

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14

15

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17

18

19

20

21

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27

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30

TABLE 21

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 22

1

2

3

4

5

6

7

8

9

10

11

TABLE 23

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 24

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

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17

18

TABLE 25

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 26

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 27

1

2

3

4

5

6

7

8

9

10

11

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14

15

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17

18

19

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21

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27

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29

30

TABLE 28

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 29

1

2

3

4

5

6

7

8

9

10

11

TABLE 30

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 31

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 32

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 33

1

2

3

4

5

6

7

8

9

10

11

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13

14

15

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17

18

19

20

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27

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29

30

TABLE 34

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 35

1

2

3

4

5

6

7

8

9

10

11

TABLE 36

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 37

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 38

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 39

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 40

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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27

28

29

30

TABLE 41

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 42

1

2

3

4

5

6

7

8

9

10

11

TABLE 43

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 44

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 45

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 46

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 47

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

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26

27

28

29

30

TABLE 48

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 49

1

2

3

4

5

6

7

8

9

10

11

TABLE 50

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 51

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 52

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 53

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 54

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

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25

26

27

28

29

30

TABLE 55

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 56

1

2

3

4

5

6

7

8

9

10

11

TABLE 57

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 58

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 59

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 60

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 61

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

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25

26

27

28

29

30

TABLE 62

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 63

1

2

3

4

5

6

7

8

9

10

11

TABLE 64

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 65

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 66

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 67

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 68

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 69

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 70

1

2

3

4

5

6

7

8

9

10

11

TABLE 71

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 72

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 73

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 74

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 75

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

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24

25

26

27

28

29

30

TABLE 76

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 77

1

2

3

4

5

6

7

8

9

10

11

TABLE 78

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 79

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 80

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 81

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 82

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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26

27

28

29

30

TABLE 83

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 84

1

2

3

4

5

6

7

8

9

10

11

TABLE 85

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 86

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 87

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 88

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 89

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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23

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25

26

27

28

29

30

TABLE 90

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 91

1

2

3

4

5

6

7

8

9

10

11

TABLE 92

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 93

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 94

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 95

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 96

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 97

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 98

1

2

3

4

5

6

7

8

9

10

11

TABLE 99

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 100

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 101

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 102

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 103

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

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23

24

25

26

27

28

29

30

TABLE 104

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 105

1

2

3

4

5

6

7

8

9

10

11

TABLE 106

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 107

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 108

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 109

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 110

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 111

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 112

1

2

3

4

5

6

7

8

9

10

11

TABLE 113

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 114

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 115

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 116

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 117

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

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22

23

24

25

26

27

28

29

30

TABLE 118

1

2

3

4

5

6

7

8

9

10

11

TABLE 119

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 120

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 121

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 122

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 123

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 124

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 125

1

2

3

4

5

6

7

8

9

10

11

TABLE 126

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 127

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 128

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 129

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 130

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 131

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 132

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 133

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 134

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 135

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 136

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 137

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 138

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 139

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 140

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A contemplated inhibitor compound is used for treating a host mammalsuch as a mouse, rat, rabbit, dog, horse, primate such as a monkey,chimpanzee or human that has a condition associated with pathologicalmatrix metalloprotease activity.

Also contemplated is use of a contemplated metalloprotease inhibitorcompound in the treatment of a disease state that can be affected by theactivity of metalloproteases TNF-α convertase. Exemplary of such diseasestates are the acute phase responses of shock and sepsis, coagulationresponses, hemorrhage and cardiovascular effects, fever andinflammation, anorexia and cachexia.

In treating a disease condition associated with pathological matrixmetalloproteinase activity, a contemplated MMP inhibitor compound can beused in the form of an amine salt derived from an inorganic or organicacid. Exemplary salts include but are not limited to the following:acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

Also, a basic nitrogen-containing group can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others to provideenhanced water-solubility. Water or oil-soluble or dispersible productsare thereby obtained as desired. The salts are formed by combining thebasic compounds with the desired acid.

Other compounds useful in this invention that are acids can also formsalts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium or with organicbases or basic quaternary ammonium salts.

In some cases, the salts can also be used as an aid in the isolation,purification or resolution of the compounds of this invention.

Total daily dose administered to a host mammal in single or divideddoses can be in amounts, for example, for 0.001 to 30 mg/kg body weightdaily and more usually 0.01 to 10 mg. Dosage unit compositions cancontain such amounts or submultiples thereof to make up the daily dose.A suitable dose can be administered, in multiple sub-doses per day.Multiple doses per day can also increase the total daily dose, shouldthis be desired by the person prescribing the drug.

The dosage regimen for treating a disease condition with a compoundand/or composition of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed can vary widely and thereforecan deviate from the preferred dosage regimen set forth above.

A compound of the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, a contemplated aromatic sulfone hydroximateinhibitor compound can be admixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulfuric acids, gelatin, acacia gum, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thentableted or encapsulated for convenient administration. Such capsules ortablets can contain a controlled-release formulation as can be providedin a dispersion of active compound in hydroxypropylmethyl cellulose. Inthe case of capsules, tablets, and pills, the dosage forms can alsocomprise buffering agents such as sodium citrate, magnesium or calciumcarbonate or bicarbonate. Tablets and pills can additionally be preparedwith enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. A contemplated aromatic sulfone hydroximate inhibitorcompound can be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

BEST MODE FOR CARRYING OUT THE INVENTION

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limiting ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 Preparation ofN-hydroxy-2-[(4-phenoxyphenyl)sulfonyl]acetamide

Part A: To a solution of 3-bromopyruvic acid hydrate (1.95 g, 11.7 mmol)cooled to zero degrees Celsius in methanol (50 mL) was added4-(phenoxy)benzenethiol (2.35 g, 11.7 mmol). The solution was stirredfor 15 minutes followed by concentration in vacuo. The residue waspartitioned between ethyl acetate and H₂O and the organic layer wasdried over magnesium sulfate. Concentration in vacuo provided the crudesulfide as a yellow solid that was used without any additionalpurification.

Part B: To a solution of the crude sulfide of part A (1.2 g, <2.6 mmol)in methanol/H₂O cooled to zero degrees Celsius was added Oxone® (3.5 g,5.72 mmol). The solution was stirred for 1 hour followed by removal ofexcess Oxone® by filtration. The filtrate was concentrated and theresidue was dissolved into ethyl acetate and washed with saturatedNaHCO₃ and saturated NaCl and dried over magnesium sulfate. Afterconcentration in vacuo the resulting residue was dissolved into methanoland thionyl chloride (1.9 mL, 26 mmol) was added. Chromatography (onsilica, ethyl acetate/hexane) provided the sulfone as a solid (350 mg,44%). MS (CI) MH⁺ calculated for C₁₅H₁₄O₅S: 307, found 307.

Part C: To a solution of the sulfone (350 mg, 1.1 mmol) in methanol (2mL) and THF (THF; 2 mL) was added 50 percent aqueous hydroxylamine (1mL). The solution was stirred overnight. Trituration with ethyl acetateprovided the title compound as a white solid (270 mg, 77%). HPLCpurity: >979. MS (CI) MH⁺ calculated for C₁₄H₁₃NO₅S: 308, found 308.

EXAMPLE 2 Preparation ofN-hydroxy-2-methyl-2-[(4-phenoxyphenyl)sulfonyl]propanamide

Part A: To a solution of 4-(phenoxy)benzenethiol (3.8 g. 18.8 mmol) inmethanol (60 mL) cooled to zero degrees Celsius was added t-butylbromoacetate (2.8 mL, 18.8 mmol) and triethylamine (2.6 mL, 19.0 mmol).The solution was stirred for 30 minutes and was then concentrated invacuo. The residue was partitioned between ethyl acetate and H₂O and theorganic layer was washed with saturated NaCl and dried over magnesiumsulfate. Concentration in vacuo provided the sulfide as an oil. To asolution of the sulfide in dichloromethane (85 mL) was addedm-chloroperbenzoic acid (13.8 g, 43.2 mmol) over 15 minutes. Thesolution was stirred at ambient temperature for 2 hours. The reactionwas quenched by the addition of aqueous Na₂SO₃. After 30 minutes thesolution was filtered through Celite®. The filtrate was washed with 25percent aqueous hydroxylamine, 1N HCl, and saturated NaCl and dried overmagnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the sulfone as a white solid (4.0 g, 68%).

Part B: To a solution of the sulfone of part A (3.2 g, 9.2 mmol) in THF(65 mL) cooled to zero degrees Celsius was added sodium hydride (730 mgof a 60 percent dispersion in mineral oil, 18.4 mmol). After 10 minutes,methyl iodide (2.28 mL, 36.8 mmol) was added dropwise and the mixturewas stirred for 18 hours at ambient temperature. The reaction wasquenched with H₂O and concentrated in vacuo. The aqueous residue wasdiluted with ethyl acetate and the organic phase was washed with H₂O anddried over Na₂SO₄. Concentration in vacuo provided the dimethyl compoundas an off-white solid (3.2 g, 92%). HPLC purity: 95%.

Part C: To a solution of the dimethyl compound of part B (3.2 g, 8.5mmol) in anisole (10 mL) was added trifluoroacetic acid (30 mL) and thesolution was stirred for 30 minutes. Concentration in vacuo followed bytrituration (ethyl ether) provided the acid as a white solid (750 mg,28%). HPLC purity: 99%. MS (CI) MH⁺ calculated for C₁₆H₁₆O₅S: 321, found321.

Part D: To a solution of the acid of part C (723 mg, 2.26 mmol) in DMF(DMF; 4.5 mL) was added N-hydroxybenzotriazoles.H₂O (HOBT; 366 mg, 2.71mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC; 476 mg, 2.49 mmol). After the solution was stirred for 1 hour atambient temperature 50 percent aqueous hydroxylamine (0.40 mL, 6.8 mmol)was added. After 15 minutes the solution was partitioned between ethylacetate and H₂O. The organic layer was washed with H₂O and saturatedNaCl and dried over Na₂SO₄. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the title compound as a white foam (434 mg,57%). HPLC purity: 99%. MS (CI) M+Li⁺ calculated for C₁₆H₁₇NO₅O: 342,found 342.

EXAMPLE 3 Preparation of 1,1-dimethylethyl ester4-[(hydroxyamino)carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylicacid

Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) inDMSO (DMSO; 20 mL) was heated to sixty-five degrees Celsius for 5 hours.The solution remained at ambient temperature for 18 hours. The solutionwas extracted with ethyl acetate and the combined organic layers werewashed with H₂O and saturated NaCl and dried over magnesium sulfate.Concentration in vacuo provided the disulfide as a yellow oil (2.3 g,quantitative yield).

Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF(100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexanes) and concentrated in vacuo to give the BOC-piperidinecompound (26.2 g, quantitative yield) as a clear, colorless oil.

Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30mL), cooled to minus seventy-eight degrees Celsius, was added n-butyllithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, theBOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) wasadded dropwise. After 1.5 hours the solution was cooled to minus sixtydegrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7mL). The solution was stirred at ambient temperature for 2 hours. Thesolution was diluted with H₂O and extracted with ethyl acetate. Theorganic layer was washed with H₂O and saturated NaCl and dried overmagnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the sulfide as an oil (1.8 g, 40%).

Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) indichloromethane (75 mL) cooled to zero degrees Celsius, was addedm-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for1.5 hours followed by dilution with H₂O and extraction withdichloromethane. The organic layer was washed with 10 percent Na₂SO₄,H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography(on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15g, 59%).

Part E: To a solution of the sulfone of part D (800 mg, 1.63 mmol) inTHF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H₂O(3 mL). The solution was heated at sixty-five degrees Celsius for 18hours. The solution was concentrated in vacuo and the residue wasdissolved in H₂O. Following acidification with 2N HCl to pH 4, thesolution was extracted with ethyl acetate and the organic layer waswashed with saturated NaCl and dried over magnesium sulfate.Concentration in vacuo provided the acid as a white foam (790 mg,quantitative yield). Analytical calculated for C₂₃H₂₇NO₇S: C, 59.86; H,5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.

Part F: To a solution of the acid of part G (730 mg, 1.58 mmol) in DMF(9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueoushydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20hours and additional N-hydroxybenzotriazole.H₂O (256 mg), EDC (424 mg)and 50 percent aqueous hydroxylamine (1.04 mL) were added. After anadditional 24 hours of stirring the solution was diluted with H₂O andextracted with ethyl acetate and the organic layer was washed withsaturated NaCl and dried over magnesium sulfate. Reverse phasechromatography (on silica, acetonitrile/H₂O) provided the title compoundas a white solid (460 mg, 61%). HPLC purity: >99%. Analytical calculatedfor C₂₃H₂₈N₂O₇S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95;H, 6.02; N, 5.81; S, 6.85.

EXAMPLE 4 Preparation ofN-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) inDMSO (20 mL) was heated to sixty-five degrees Celsius for 5 hours. Thesolution remained at ambient temperature for 18 hours. The solution wasextracted with ethyl acetate and the combined organic layers were washedwith H₂O and saturated NaCl and dried over magnesium sulfate.Concentration in vacuo provided the disulfide as a yellow oil (2.3 g,quantitative yield).

Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF(100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (on silica, ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound as a clear, colorless oil (26.2 g, quantitative yield).

Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30mL), cooled to minus seventy-eight degrees Celsius, was added n-butyllithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, theBOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) wasadded dropwise. After 1.5 hours the solution was cooled to minus 60degrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7mL) was added. The solution was stirred at ambient temperature for 2hours. The solution was diluted with H₂O and extracted with ethylacetate. The organic layer was washed with H₂O and saturated NaCl anddried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as an oil (1.8 g, 40%).

Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) indichloromethane (75 mL) cooled to zero degrees C., was addedm-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for1.5 hours followed by dilution with H₂O and extraction withdichloromethane. The organic layer was washed with 10 percent Na₂SO₃,H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography(on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15g, 59%).

Part E: To a solution of the sulfone of part D (800 mg, 1.63 mmol) inTHF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H₂O(3 mL). The solution was heated at sixty-five degrees Celsius for 18hours. The solution was concentrated in vacuo and the residue wasdissolved in H₂O. Following acidification with 2N HCl to pH 4, thesolution was extracted with ethyl acetate and the organic layer waswashed with saturated NaCl and dried over magnesium sulfate.Concentration in vacuo provided the acid as a white foam (790 mg,quantitative yield). Analytical calculated for C₂₃H₂₇NO₇S: C, 59.86; H,5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.

Part F: To a solution of the acid of part G (730 mg, 1.58 mmol) in DMF(9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueoushydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20hours and additional HOBT (256 mg), EDC (424 mg) and 50 percent aqueoushydroxylamine (1.04 mL) were added. After an additional 24 hours ofstirring the solution was diluted with H₂O, and extracted with ethylacetate. The organic layer was washed with saturated NaCl and dried overmagnesium sulfate. Reverse phase HPLC (acetonitrile/H₂O) provided thehydroxamate as a white solid (460 mg, 61%). HPLC purity: >99%.Analytical calculated for C₂₃H₂₈N₂O₇S: C, 57.97; H, 5.92; N, 5.88; S,6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.

Part G: Into a solution of the hydroxamate of part F (385 mg, 0.808mmol) in ethyl acetate (25 mL), cooled to zero degrees Celsius, wasbubbled HCl gas for 5 minutes. After standing for 30 minutes, thesolution was concentrated in vacuo. Trituration with ethyl etherprovided the title compound as a white solid (330 mg, quantitativeyield). MS (CI) MH⁺ calculated for C₁₈H₂₀N₂O₅S: 377, found 377. HRMScalculated for C₁₈H₂₀N₂O₅S: 377.1171, found 377.1170. Analyticalcalculated for C₁₈H₂₀N₂O₅S.1.1HCl.0.25H₂O; C, 51.35; H, 5.17; N, 6.65;S, 7.62; Cl, 9.26. Found: C, 51.58; H, 5.09; N, 6.55; S, 8.02; Cl, 9.09.

EXAMPLE 5 Preparation of (E)N-hydroxy-2-[(4-phenoxyphenyl)sulfonyl]-3-phenyl-2-propenamide

Part A: To a solution of 4-(phenoxy)benzenethiol (5.00 g, 24.7 mmol) inmethanol (100 mL) cooled to zero degrees Celsius was addedt-butylbromoacetate (3.99 mL, 24.7 mmol). Following the addition oftriethylamine (3.60 mL, 25.8 mmol) the solution was stirred for 40minutes The solution was concentrated in vacuo and the resulting residuewas dissolved in ethyl acetate and washed with H₂O and saturated NaCland dried over Na₂SO₄. Concentration in vacuo provided the sulfide as anoil (7.9 g, quantitative yield).

Part B: To a solution of the sulfide of part A (7.9 g, 24.7 mmol) inmethanol (180 mL) and H₂O (20 mL) was added Oxone® (38.4 g, 62.5 mmol)and the mixture was stirred for 22 hours. The mixture was acidified topH 4 with 2.5N NaOH and decanted to remove insoluble salts. Thedecantate was concentrated to one-half volume and partitioned betweenethyl acetate and H₂O. The organic layer was washed with H₂O andsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane) provided the sulfone as a yellow solid (5.79 g, 67%).

Part C: To a solution of the sulfone of part B (2.5064 g, 7.20 mmol) andbenzaldehyde (0.748 mL, 7.36 mmol) in benzene (20 mL) were added aceticacid (0.15 mL) and piperidine (0.05 mL). The solution was heated toreflux for 2 hours and the condensate was collected via a Dean-Starktrap. After an additional 1.5 hours of reflux, the solution was returnedto ambient temperature and stirred for 18 hours. The solution wasdiluted with ethyl acetate and washed with H₂O and saturated NaCl anddried over Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane)followed by trituration (ethyl ether/hexane) provided the unsaturatedsulfone as a white solid (1.97 g, 73%). HPLC purity: >98%.

Part D: Into a solution of the unsaturated sulfone of part C (0.5053 g,1.16 mmol) was bubbled HCl gas for 1 hour. The solution was concentratedin vacuo and the residue was dissolved into ethyl acetate and washedwith H₂O and dried over Na₂SO₄. Concentration in vacuo provided the acidas an oil (0.41 g, 93%).

Part E: To a solution of the acid of part D (461 mg, 1.21 mmol) wasadded thionyl chloride (3.0 mL) and the solution was heated to onehundred degrees Celsius for 1 hour. Concentration in vacuo provided theacid chloride as an amber oil (380 mg, 79%).

Part F: To a solution of the acid chloride of part E (380 mg, 0.95 mmol)in THF (20 mL) was added 50 percent aqueous hydroxylamine (1.7 mL, 9.5mmol). The solution was stirred at zero degrees Celsius for 1 hour. Thesolution was diluted with ethyl acetate, washed with H₂O and saturatedNaCl, and dried over Na₂SO₄. Reverse phase chromatography (on silica,acetonitrile/H₂O) followed by trituration (ethyl ether/hexane) providedthe title compound as a white solid (131 mg, 35%). HPLC purity: >97%.

EXAMPLE 6 Preparation ofN-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) inDMSO (20 mL) was heated to 65 degrees Celsius for 5 hours. The solutionremained at ambient temperature for 18 hours. The solution was extractedwith ethyl acetate and the combined organic layers were washed with H₂Oand saturated NaCl, and dried over magnesium sulfate. Concentration invacuo provided the disulfide as a yellow oil (2.3 g, quantitativeyield).

Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF(100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound as a clear, colorless oil (26.2 g, quantitative yield).

Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) in THF (30mL), cooled to minus seventy-eight degrees Celsius, was added n-butyllithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, theBOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) wasadded dropwise. After 1.5 hours the solution was cooled to minus sixtydegrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7mL) was added. The solution was stirred at ambient temperature for 2hours. The solution was diluted with H₂O and extracted with ethylacetate. The organic layer was washed with H₂O and saturated NaCl anddried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as an oil (1.8 g, 40%).

Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) indichloromethane (75 mL) cooled to zero degrees Celsius, was addedm-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for1.5 hours followed by dilution with H₂O and extraction withdichloromethane. The organic layer was washed with 10 percent Na₂SO₄,H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography(on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15g, 59%).

Part E: Into a solution of the sulfone of part D (3.56 g, 7.0 mmol) inethyl acetate (100 mL) cooled to zero degrees Celsius was bubbled HClgas for 5 minutes. Concentration in vacuo followed by trituration withethyl ether provided the amine hydrochloride salt as a white solid (3.5g, quantitative yield). MS (CI) MH⁺ calculated for C₂₀H₂₃NO₅S: 390,found 390.

Part F: To a solution of the amine hydrochloride salt of part E (2.6 g,6 mmol) and K₂CO₃ (1.66 g, 12 mmol) in DMF (50 mL) was added propargylbromide (892 mg, 6 mmol) and the solution was stirred at ambienttemperature for 4 hours. The solution was diluted with H₂O and extractedwith ethyl acetate. The combined organic layers were washed withsaturated NaCl and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/hexane) provided the propargyl amine as a whitesolid (2.15 g, 82%).

Part G: To a solution of the propargyl amine of part F (2.15 g, 5 mmol)in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) andthe solution was heated at 65 degrees Celsius for 48 hours. The solutionwas concentrated in vacuo and the aqueous residue was acidified to a pHvalue of 5. Vacuum filtration of the resulting precipitate provided theacid as a white solid (2.04 g, quantitative yield).

Part H: To a solution of the acid of part G (559 mg, 1.4 mmol) indichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed bybromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP®; 718 mg,1.54 mmol). The solution was stirred at ambient temperature for 4 hours.The solution was diluted with H₂O and extracted with dichloromethane.The organic layer was washed with saturated NaCl and dried overmagnesium sulfate. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the hydroxamate as a white solid (140 mg,25%). Analytical calculation for C₂₁H₂₂N₂O₅S: C, 60.85; H, 5.37; N,6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.

Part I: To a solution of the hydroxamate of part H (121 mg, 0.292 mmol)in methanol (2 mL) cooled to zero degrees Celsius was added acetylchloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring atambient temperature for 30 minutes the solution was concentrated under astream of N₂. Trituration with ethyl ether provided the title compoundas a white solid (107 mg, 81%). Analytical calculation forC₂₁H₂₂N₂O₅S.HCl.0.3H₂O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H,5.37; N, 6.07.

EXAMPLE 7 Preparation ofN-[4-[[2-(hydroxyamino)-2-oxoethyl]sulfonyl]phenyl]benzamide

Part A: To a suspension of 2-(4-aminophenylthio)acetic acid (20.00 g,0.109 mmol) in methanol (100 mL) cooled to zero degrees Celsius wasadded thionyl chloride (24.0 mL, 0.327 mmol) dropwise. Additionalmethanol was added (100 mL) and the suspension was heated to reflux for2 hours. The solution was concentrated in vacuo and the residue wasdissolved into H₂O and neutralized with saturated NaHCO₃. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere washed with saturated NaCl and dried over Na₂SO₄. Concentration invacuo provided the methyl ester as a dark purple oil (22.75 g,quantitative yield). HPLC purity: 99%.

Part B: To a solution of the methyl ester of part A (5.00 g, 25.35 mmol)and triethylamine (7.07 mL, 50.70 mmol) in dichioromethane (50 mL) wasadded benzoyl chloride (3.24 mL, 27.89 mmol) and the solution wasstirred at ambient temperature for 2 hours. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate, THF and H₂O. The organic layer was washed with H₂O andsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe benzamide as a purple solid (7.06 g, 92%). HPLC purity: 98%. MS (CI)M+Li⁺ calculated for C₁₆H₁₅NO₃S: 308, found 308.

Part C: To a solution of the benzamide of part B (4.00 g, 13.27 mmol) inTHF (100 mL) and H₂O (10 mL) cooled to zero degrees Celsius was addedOxone® (potassium monopersulfate; 24.47 g, 39.81 mmol). The slurry wasstirred overnight (about eighteen hours) at ambient temperature. Themixture was filtered to remove excess Oxone® and the filtrate wasconcentrated in vacuo. The residue was dissolved into ethyl acetate andwashed with H₂O and saturated NaCl, and then dried over Na₂SO₄.Concentration in vacuo provided the sulfone as a pink solid (4.11 g,93%). HPLC purity: 98%. MS (CI) M+Li⁺ calculated for C₁₆H₁₅NO₅S: 340,found 340.

Part D: To a solution of the sulfone of part C (400 mg, 1.2 mmol) in THF(9 mL) was added 50 percent aqueous hydroxylamine (5.0 mL). The solutionwas stirred for 8 hours and was concentrated in vacuo. Trituration withhot ethyl ether provided the title compound as an off-white solid (348mg, 78%). HPLC purity: 97%. MS (CI) MH⁺ calculated for C₁₇H₁₄N₂O₅S: 335,found 335.

EXAMPLE 8 Preparation ofN-[4-[[2-(hydroxyamino)-2-oxo-1-(piperidin-4-yl)ethyl]sulfonyl]phenyl]-benzamide,monohydrochloride

Part A: To a solution of diethanolamine (22.16 g, 0.211 mol) in THP (100mL) cooled to zero degrees Celsius was added di-t-butyl dicarbonate(46.0 g, 0.211 mol) and the solution was stirred at ambient temperaturefor 20 hours. The solution was concentrated in vacuo and the resultingresidue was filtered through a silica pad (5 percent methanol/95 percentdichloromethane) to provide the diol as a clear oil (45.06 g,quantitative yield). MS (CI) MH⁺ calculated for C₉H₁₉O₄S: 206, found206.

Part B: To a suspension of 2-(4-aminophenylthio)acetic acid (20.00 g,0.109 mmol) in methanol (100 mL) cooled to zero degrees Celsius thionylchloride (24.0 mL, 0.327 mmol) was added dropwise. After additionalmethanol was added (100 mL), the suspension was heated to reflux for 2hours. The composition was concentrated in vacuo, the residue wasdissolved in H₂O and neutralized with saturated NaHCO₃. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere washed with saturated NaCl and dried over Na₂SO₄. Concentration invacuo provided the methyl ester as a dark purple oil (22.75 g,quantitative yield). HPLC purity: 99%.

Part C: To a solution of the methyl ester of part B (5.00 g, 25.35 mmol)and triethylamine (7.07 mL, 50.70 mmol) in dichloromethane (50 mL) wasadded benzoyl chloride (3.24 mL, 27.89 mmol) and the solution wasstirred at ambient temperature for 2 hours. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate, THF and H₂O. The organic layer was washed with H₂O andsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe benzamide as a purple solid (7.06 g, 92%). HPLC purity: 98%.

Part D: To a solution of the benzamide of part C (4.00 g, 13.27 mmol) inTHF (100 mL) and H₂O (10 mL) cooled to zero degrees Celsius was addedOxone® (24.47 g, 39.81 mmol). The slurry was stirred overnight (abouteighteen hours) at ambient temperature. The mixture was filtered toremove excess Oxone® and the filtrate was concentrated in vacuo. Theresidue was dissolved into ethyl acetate and washed with H₂O andsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe sulfone as a pink solid (4.11 g, 93%). HPLC purity: 98%.

Part E: To a solution of the diol of part A (1.03 g, 5.00 mmol) and themethyl ester of part D (2.00 g, 6.00 mmol) in THF (100 mL) was added the1,1′-(azodicarbonyl)dipiperidine (5.05 g, 20.00 mmol). To this slurrywas added trimethyl phosphine (20.00 mL of a 1.0M solution in THF, 20.00mmol). The mixture stirred for 1 hour at ambient temperature and thenwas heated at 40 degrees Celsius for 18 hours. After the slurry returnedto ambient temperature, ethyl ether was added and the insoluble solidswere removed by filtration. The filtrate was concentrated in vacuo andthe resulting residue was dissolved into ethyl acetate, washed with H₂Oand saturated NaCl, and then dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the piperidine compound as ayellow solid (600 mg, 24%). MS (CI) MH⁺ calculated for C₂₅H₃₀N₂O₇S: 503,found 503.

Part F: To a solution of the piperidine compound of part E (950 mg, 1.89mmol) in THF (10 mL) was added potassium silanolate (970 mg, 7.56 mmol)and the solution was stirred at ambient temperature for 72 hours. Thesolution was diluted with H₂O, acidified to pH 2 with 1M HCl, andextracted with ethyl acetate. The combined organic layers were washedwith saturated NaCl and dried over Na₂SO₄. Concentration in vacuoprovided the acid as a yellow solid (772 mg, 84%).

Part G: To a solution of the acid of part F (772 mg, 1.4B mmol) in DMF(9 mL) was added HOBT (240 mg, 1.77 mmol), 4-methylmorpholine (0.488 mL,4.44 mmol), O-tetrahydropyranyl hydroxyamine (538 mg, 4.54 mmol) and EDC(397 mg, 2.07 mmol). The solution stirred at ambient temperature for 2hours. Following concentration in vacuo the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane) provided the protected hydroxylamine as a white solid(608 mg, 70%). HPLC purity: >99%).

Part H: To a solution of the protected hydroxylamine of part G (596 g,1.01 mmol) in dioxane (3 mL) and methanol (1 mL) was added 4M HCl indioxane (2.50 mL, 10.14 mmol) and the solution stirred for 50 minutes atambient temperature. Trituration with ethyl ether provided the titlecompound as a white solid (433 mg, 98%). HPLC purity: 98%. MS (CI) MH⁺calculated for C₁₉H₂₁N₃O₅S: 404, found 404.

EXAMPLE 9 Preparation ofN-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF(100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirredovernight (about eighteen hours) at ambient temperature and concentratedin vacuo to yield a light oil. The oil was filtered through silica gel(ethyl acetate/hexanes) and concentrated in vacuo to give theBOC-piperidine compound as a clear, colorless oil (26.2 g, quantitativeyield).

Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO(500 mL) was heated to 65 degrees Celsius for 6 hours. The reaction wasquenched into wet ice and the resulting solid was collected by vacuumfiltration to provide the disulfide as a white solid (34.4 g, 68.9%).

Part C: To a solution of the BOC-piperdine compound of part A (16 g, 62mmol) in THF (300 mL) cooled to minus 50 degrees Celsius was addedlithium diisopropylamide (41.33 mL, 74 mmol) and the solution wasstirred for 1.5 hours at zero degrees Celsius. To this solution wasadded the disulfide of part B (15.77 g, 62 mmol), and the resultingsolution was stirred at ambient temperature for 20 hours. The reactionwas quenched with the addition of H₂O and the solution was concentratedin vacuo. The aqueous residue was extracted with ethyl acetate and theorganic layer was washed with 0.5N KOH, H₂O, and saturated NaCl.Chromatography (on silica, hexane/ethyl acetate) provided the sulfide asan oil (18.0 g, 75%).

Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) indichloromethane (500 mL) cooled to zero degrees Celsius was added3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirredfor 20 hours. The solution was diluted with H₂O and extracted withdichloromethane. The organic layer was washed with 10 percent Na₂SO₃,H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography(on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7g, 60%).

Part E: Into a solution of the sulfone of part D (10 g, 24.0 mmol) inethyl acetate (250 mL) was bubbled HCl gas for 10 minutes followed bystirring at ambient temperature for 4 hours. Concentration in vacuoprovided the amine hydrochloride salt as a white solid (7.27 g, 86%).

Part F: To a solution of the amine hydrochloride salt of part E (5.98 g,17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solutionwas stirred for 4 hours at ambient temperature. The solution waspartitioned between ethyl acetate and H₂O, and the organic layer waswashed with H₂O and saturated NaCl and dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexane) provided the propargylamine as a yellow oil (5.2 g, 86%).

Part G: To a solution of the propargyl amine of part F in DMF (15 mL)was added thiophenol (0.80 mL, 7.78 mmol) and CsCO₃ (2.79 g, 8.56 mmol)and the solution was heated to 70 degrees Celsius for 6 hours. Thesolution was partitioned between ethyl ether and H₂O. The organic layerwas washed with H₂O and saturated NaCl, and dried over magnesiumsulfate. Chromatography (on silica, ethyl acetate/hexane) provided theS-phenoxyphenyl compound as an oil (1.95 g, 56%).

Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06mmol) in ethanol (21 mL) and H₂O (3.5 mL) was added KOH (1.37 g, 24.5mmol) and the solution was heated to 105 degrees Celsius for 4.5 hours.The solution was acidified to a pH value of 1 with concentrated HClsolution and then concentrated to provide the acid as a yellow residuethat was used without additional purification (1.82 g).

Part I: To a solution of the acid of part H (1.82 g, 4.06 mmol) inacetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine(723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To thisstirring solution was added EDC (1.18 g, 6.17 mmol) and the solution wasstirred for 18 hours. The solution was partitioned between H₂O and ethylacetate. The organic layer was washed with H₂O, saturated NaHCO₃ andsaturated NaCl and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/hexane) provided the protected hydroxamate as awhite solid (1.32 g, 63%).

Part J: To a solution of the protected hydroxamate of part I (9.65 g,18.7 mmol) in methanol (148 mL) cooled to zero degrees Celsius was addedacetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45minutes at ambient temperature. Concentration in vacuo followed bytrituration with ethyl ether provided the title compound as a whitesolid (8.10 g, 94%). MS (CI) MH⁺ calculated for C₂₁H₂₂N₂O₄S₂: 431, found431.

EXAMPLE 10 Preparation of4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the propargyl amine of Example 9, part F (7.0g, 19.8 mmol) in DMF (30 mL) were added sesamol (5.52 g, 40 mmol) andpotassium carbonate (5.52 g, 40 mmol), and the solution was heated to 85degrees Celsius for 48 hours. The solution was partitioned between ethylacetate and H₂O. The organic layer was dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexane) provided the sulfide asan oil (9.38 g, quantitative yield).

Part B: To a solution of the sulfide of part A (2.72 g, 5.92 mmol) inethanol (30 mL) and H₂O (5 mL) was added potassium hydroxide (2.0 g, 36mmol) and the solution was heated to reflux for 4 hours. The solutionwas acidified to pH=3 with concentrated HCl. The solution wasconcentrated in vacuo and the residue was dissolved in acetonitrile (30mL). To this solution was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine(1.05 g, 9.0 mmol), triethylamine (1 mL) and EDC (1.72 g, 9.0 mmol) andthe solution was stirred at ambient temperature for 18 hours. Thesolution was concentrated in vacuo and diluted with saturated NaHCO₃ andextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as an oil (2.86 g, 93%).

Part C: To a solution of the protected hydroxamate of part B (2.86 g,5.27 mmol) in methanol (40 mL) was added acetyl chloride (1.13 mL, 15.8mmol) and the solution was stirred for 3 hours. The solution wasconcentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O(HCl)) provided the title compound as a white solid (2.2g, 84%). MS (CI) MH⁺ calculated for C₂₂H₂₂N₂O₇S: 459, found 459.

EXAMPLE 11 Preparation ofTetrahydro-N-hydroxy-4-[[4-(4-phenyl-1-piperidinyl)phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a solution of Na (8.97 g, 390 mmol) in methanol (1 L) at zerodegrees Celsius were added 4-fluorothiophenol (50 g, 390 mmol) andmethyl chloroacetate (34.2 mL, 390 mmol), and the solution was stirredfor 4 hours at ambient temperature. The solution was filtered to removesalts and the filtrate was concentrated in vacuo to provide the sulfideas a colorless oil (75.85 g, 97%).

Part B: To a solution of the sulfide of part A (75.85 g, 380 mmol) inmethanol (1 L) and H₂O (100 mL) was added Oxone® (720 g, 1.17 mol) andthe solution was stirred for 2 hours. The reaction mixture was filteredto remove the excess salts and the filtrate was concentrated in vacuo.The residue was dissolved into ethyl acetate and washed with H₂O,saturated NaHCO₃ and saturated NaCl, and then dried over magnesiumsulfate. Concentration in vacuo provide the sulfone as white solid(82.74 g, 94%)

Part C: To a solution of the sulfone of part B (28.5 g, 123 mmol) inN,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g,270 mmol), bis-(2-bromoethyl)ether (19.3 mL, 147 mmol),4-dimethylaminopyridine (750 mg, 6 mmol) and tetrabutylammonium bromide(1.98 g, 6 mmol), and the solution was stirred at ambient temperaturefor 72 hours. The solution was poured into 1N HCl (300 mL) and theresulting precipitate was collected by vacuum filtration.Recrystallization (ethyl acetate/hexane) provided the tetrahydropyrancompound as a beige solid (28.74 g, 77%).

Part D: To a solution of the tetrahydropyran compound of part C (1.21 g,4.0 mmol) in DMSO (10 mL) were added Cs₂CO₃ (3.26 g, 10.0 mmol) and4-phenylpiperidine (640 mg, 4.0 mmol), and the solution was heated to 90degrees Celsius for 2 hours. The solution was diluted with H₂O andextracted with ethyl acetate. The organic layer was washed with 5percent aqueous KHSO₄, saturated NaHCO₃ and saturated NaCl and driedover magnesium sulfate. Concentration in vacuo provided the amine as awhite solid (1.2 g, 67%).

Part E: To a solution of the amine of part D (815 mg, 1.84 mmol) inmethanol (5 mL) and THF (5 mL) was added 50 percent aqueous NaOH (2 mL)and the solution was stirred for 18 hours at ambient temperature. Thesolution was concentrated in vacuo and the residue was diluted with H₂Oand acidified to a pH value of 7. The resulting precipitate wascollected by vacuum filtration to provide the acid as a white solid (680mg, 86%).

Part F: To a solution of the acid of part E (620 mg, 1.44 mmol) indichloromethane (10 mL) and DMF (3 mL) were added PyBroP (810 mg, 1.73mmol), N-methylmorpholine (0.5 mL, 4.3 mmol) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (190 mg, 1.59 mmol) and thesolution was stirred for 4 hours at ambient temperature. The solutionwas concentrated in vacuo, the residue dissolved into ethyl acetate andwashed with H₂O and saturated NaCl, and then dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the protectedhydroxamate as a white solid (630 mg, 83%6). MS (CI) MH⁺ calculated forC₂₈H₃₆N₂O₆S: 529, found 529.

Part G: To a solution of the protected hydroxamate of part F (600 mg,1.14 mmol) in dioxane (1.5 mL) and methanol (1.5 mL) was added 4N HCl indioxane (1.5 mL), and the solution was stirred for 2 hours. The solutionwas poured into ethyl ether and the resulting precipitate was collectedby vacuum filtration to provide the title compound as a beige solid (500mg, 91%). MS (CI) M+Li⁺ calculated for C₂₃H₂₈N₂O₅S: 445, found 445.

EXAMPLE 12 Preparation of1-acetyl-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperidinecarboxamide

Part A: To a solution of the sulfone of Example 6, part D (2.75 g, 5.6mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (2.25 g, 56mmol), and the solution was heated to 70 degrees Celsius for 18 hours.The solution was concentrated in vacuo, the residue was dissolved intoH₂O and extracted with ethyl ether. The aqueous solution was acidifiedto a pH value of 2 and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate. Concentration in vacuo provided thecrude acid as a solid. A solution of the acid in dichloromethane (6 mL)and trifluoroacetic acid (6 mL) was stirred for 1 hour at ambienttemperature. Concentration in vacuo provided the amine hydrochloridesalt as a solid (2.3 g, quantitative yield).

Part B: To a solution of the amine hydrochloride salt of part A (2.3 g,<5.6 mmol) in acetone (10 mL) and H₂O (10 mL) cooled to zero degreesCelsius were added triethylamine (1.17 mL, 8.4 mmol) and acetyl chloride(0.60 mL, 8.4 mmol), and the solution was stirred at ambient temperaturefor 18 hours. The solution was concentrated in vacuo to remove theacetone and the aqueous solution was extracted with ethyl ether. Theaqueous layer was acidified to a pH value of 2 and extracted with ethylacetate. The organic layer was dried over magnesium sulfate andconcentration in vacuo provided the N-acetyl compound as a white solid(1.5 g, 65.2%).

Part C: To a solution of the N-acetyl compound of part B (0.6 g, 1.49mmol) in DMF (10 mL) were added EDC (401 mg, 2.1 mmol) followed by 50percent aqueous hydroxylamine (0.9 mL) and 4-methylmorpholine (0.7 mL,6.4 mmol), and the solution was stirred for 18 hours at ambienttemperature. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate. The organic layer was washed with H₂O anddried over magnesium sulfate. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the title compound as a white solid (101 mg,16%). MS (CI) MH⁺ calculated for C₂₀H₂₂N₂O₆S: 419, found 419.

EXAMPLE 13 Preparation of4-[[4-(cyclohexylthio)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the propargyl amine of Example 9, part F (6.5g, 18.4 mmol) in DMF (10 mL) were added potassium carbonate (3.81 g,27.6 mmol) and cyclohexyl mercaptan (3.37 mL, 27.6 mmol). The solutionwas heated to 100 degrees Celsius for 6.5 hours. The solution wasdiluted with H₂O and extracted with ethyl acetate. The organic layerswere dried over magnesium sulfate. Chromatography (on silica,hexane/ethyl acetate) provided the sulfide as a yellow oil (6.05 g,73%).

Part B: To a solution of the sulfide of part B (612 mg, 1.4 mmol) inethanol (8.4 mL) and H₂O (1.4 mL) was added potassium hydroxide (470 mg,8.4 mmol), and the solution was refluxed for 3 hours. The solutionacidifed to a pH value of 3 and was concentrated in vacuo. The residuewas dissolved into acetonitrile (10 mL) and to this solution were addedO-tetrahydro-2H-pyran-2-yl-hydroxylamine (230 mg, 2.0 mmol) andtriethylamine (0.5 mL) followed by EDC (380 mg, 2.0 mmol), and thesolution was stirred at ambient temperature for 18 hours. The solutionwas concentrated in vacuo and the residue was diluted with saturatedNaHCO₃ and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the protected hydroxamate as an oil (246 mg, 34%).

Part C: To a solution of the protected hydroxamate of part B (246 mg,0.47 mmol) in methanol (4 mL) was added acetyl chloride (0.11 mL, 1.5mmol), and the solution was stirred at ambient temperature for 3 hours.After concentration in vacuo, reverse phase chromatography (on silica,acetonitrile/H₂O(HCl)) provided the title compound as a white solid (223mg, quantitative yield).

EXAMPLE 14 Preparation ofN-hydroxy-1-methyl-4-[(phenoxyphenyl)sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the sulfone of Example 6, part D (2.67 g, 5.5mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL),and the solution was stirred at ambient temperature for 2 hours. Thesolution was concentrated in vacuo and the residue was triturated withethyl ether to provide the crude amine trifluoroacetic acid salt. To asolution of the crude amine salt in methanol (10 mL) were addedformaldehyde (37 percent aqueous solution, 2.0 mL, 27.5 mmol) and boranepyridine (2.2 mL, 22 mmol), and the solution was stirred at ambienttemperature for 18 hours. The solution was concentrated in vacuo. Theresidue was dissolved into ethyl acetate, washed with H₂O and dried overmagnesium sulfate. Concentration in vacuo provided the N-methyl compoundas a yellow oil (2.17 g, 98%).

Part B: To a solution of the N-methyl compound of part A (2.17 g, 5.4mmol) in ethanol (10 mL) and THF (10 mL) was added NaOH (2.0 g, 50mmol), and the reaction mixture was stirred at minus 65 degrees Celsiusfor 18 hours. The solution was concentrated in vacuo. The residue wasdissolved into H₂O and extracted with ethyl ether. The aqueous solutionwas acidified to a pH value of 2 and the resulting solid was collectedby vacuum filtration to provide the acid as a white solid (1.8 g, 90%).

Part C: To a solution of the acid of part B (0.5 g, 1.3 mmol) in DMF (10mL) were added EDC (1.06 g, 5.5 mmol) followed byO-tetrahydro-2H-pyran-2-yl-hydroxylamine (490 mg, 4.2 mmol) and4-methylmorpholine (0.76 mL) and the solution was stirred at ambienttemperature for 18 hours. The solution was concentrated in vacuo and theresidue was dissolved into ethyl acetate, washed with H₂O and dried overmagnesium sulfate. Concentration in vacuo provided the crude protectedhydroxamate. To a solution of the crude hydroxamate in methanol (10 mL)was added acetyl chloride (0.28 mL, 3.9 mmol), and the solution wasstirred for 3 hours at ambient temperature. The solution wasconcentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O (0.0125% HCl) provided the title compound as a whitesolid (261 mg, 46%). MS (CI) MH⁺ calculated for C₁₉H₂₂N₂O₅S: 391, found391.

EXAMPLE 15 Preparation ofN-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the propargyl amine of Example 9, part F (2.00g, 5.66 mmol) in DMF (10 mL) were added cesium carbonate (4.7 g, 14.5mmol) and 4-methoxythiophenol (1.80 g, 14.5 mmol), and the solution washeated to 95 degrees Celsius for 24 hours. The solution was diluted withethyl acetate and washed with 1N NaOH and saturated NaCl, and then driedover magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the phenoxy compound as a solid (2.67 g, quantitative yield).

Part B: To a solution of the phenoxy compound of part A (2.40 g, 5.25mmol) in ethanol (30 mL) and H₂O (6 mL) was added potassium hydroxide(2.0 g, 31.37 mmol), and the solution was heated to reflux for 4 hours.The solution was acidified with concentrated HCl to a pH value of 3 andthe residue was collected by vacuum filtration to provide the crude acidthat was carried on without additional purification.

Part C: To a solution of the acid of part B (2.25 g, 5.25 mmol) inacetonitrile (30 mL) were added triethylamine (1 mL) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.34 g, 9.0 mmol). After thesolution was stirred for 15 minutes, EDC (1.72 g, 9.0 mmol) was addedthe solution was stirred at ambient temperature for 18 hours. Thesolution was concentrated in vacuo and the residue was dissolved intoethyl acetate. The ethyl acetate solution was washed with saturatedNaHCO₃, H₂O and saturated NaCl and dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexane) provided the protectedhydroxamate as a white solid (0.93 g, 33%).

Part D: To a solution of the protected hydroxamate of part C (0.93 g,1.7 mmol) in methanol (15 mL) was added acetyl chloride (0.36 mL, 5.1mmol) and the solution was stirred for 3 hours. The solution wasconcentrated in vacuo to provide the title compound as a white solid(650 mg, 82%). Analytical calculation for C₂₂H₂₄N₂O₆S HCl: C, 54.84; H,5.24; N, 5.82; S, 6.67; Cl, 6.67. Found: C, 53.10; H, 5.07; N, 5.59; S,7.04; Cl, 6.32.

EXAMPLE 16 Preparation of4-[[4-(4-butoxy-1-piperidinyl)phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a solution of the tetrahydropyran compound of Example 11,part C (1.95 g, 6.46 mmol) in DMSO (25 mL) were added Cs₂CO₃ (7.4 g,22.6 mmol) and 4-butoxypiperidine (1.25 g, 6.46 mmol) and the solutionwas heated to 90 degrees Celsius for 1 hour. The solution was quenchedwith H₂O and extracted with ethyl acetate. The organic layer was washedwith 5 percent aqueous KHSO₄, saturated NaHCO₃ and saturated NaCl, anddried over magnesium sulfate. Chromatography (on silica, ethylacetate/dichloromethane) provided the amine as a yellow oil (1.85 g,65%).

Part B: To a solution of the amine of part A (1.65 g, 3.76 mmol) in THF(10 mL) was added potassium trimethylsilanolate (530 mg, 4.13 mmol), andthe solution was stirred for 22 hours at ambient temperature. Thesolution was concentrated in vacuo and the crude residue was used as isin the next reaction.

Part C: To a solution of the crude acid of part B (1.74 g, 3.76 mmol) indichloromethane (10 mL) were added PyBroP (2.10 g, 4.51 mmol),N-methylmorpholine (1.24 mL, 11.3 mmol) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (484 mg, 4.14 mmol), and thesolution was stirred for 30 minutes at ambient temperature. The solutionwas concentrated in vacuo. The residue was dissolved into ethyl acetateand washed with H₂O and saturated NaCl, and dried over magnesiumsulfate. Chromatography (on silica, ethyl acetate/hexane/methanol)provided the protected hydroxamate as a colorless oil (1.5 g, 76% overtwo steps).

Part D: To a solution of the protected hydroxamate of part C (1.25 g,2.4 mmol) in dioxane (3 mL) was added 4N HCl in dioxane (3 ml), and thesolution was stirred for 15 minutes. After methanol (3 mL) was added thesolution was stirred for 5 hours at ambient temperature. The solutionwas poured into ethyl ether and the resulting precipitate was collectedby vacuum filtration to provide the title compound as a white solid (1.0g, 88%). MS (CI) MH⁺ calculated for C₂₁H₃₂N₂O₆S: 441, found 441.

EXAMPLE 17 Preparation of1-cyclopropyl-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 6, partE (2.13 g, 5.0 mmol) in methanol (25 mL) was added 3A molecular sieves,acetic acid (2.86 mL, 50 mmol) and the solution was stirred for 5minutes. To this solution was added((1-ethyoxycyclopropyl)oxy)-trimethylsilane (6.08 mL, 30 mmol) followedby sodium cyanoborohydride (1.41 g, 22.0 mmol), and the solution washeated to reflux for 18 hours. The excess salts and sieves werecollected by filtration and the filtrate was concentrated in vacuo. Theresidue was diluted with ethyl acetate and washed with 1N NaOH, H₂O andsaturated NaCl, and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/hexane) provided the cyclopropyl amine as a whitesolid (1.90 g, 86%).

Part B: To a solution of the cyclopropyl amine of part A (1.9 g, 4.2mmol) in THF (12 mL) and ethanol (12 mL) was added NaOH (1.71 g, 4.3mmol) in H₂O (10 mL), and the solution was heated to 62 degrees Celsiusfor 20 hours. The solution was concentrated in vacuo and the residue wasdiluted with H₂O and acidified to a pH value of 5 with 1N HCl. Theresulting solid was collected by vacuum filtration to provide the acidas a white solid (1.49 g, 82%). MS (CI) MH⁺ calculated for C₂₁H₂₃NO₅S:402, found 402. HRMS calculated for C₂₁H₂₃NO₅S: 402.1375, found402.1350.

Part C: To a solution of the acid of part C (1.49 g, 3.4 mmol) indichloromethane (50 mL) was added triethylamine (1.42 mL, 10.21 mmol)followed by 50 percent aqueous hydroxylamine (2.25 mL, 34.0 mmol) andPyBroP (3.17 g, 6.8 mmol), and the solution was stirred for 72 hours.The mixture was diluted with H₂O and the organic layer was separated,washed with saturated NaCl and dried over magnesium sulfate.Concentration in vacuo followed by reverse phase chromatography (onsilica, acetonitrile/H₂O) provided the hydroxamate.

The hydrochloride salt was prepared by dissolving the free base (830 mg,2.0 mmol) in methanol (20 mL) followed by the addition of acetylchloride (0.17 mL, 2.0 mmol). The solution was stirred for 10 minutes atzero degrees Celsius. The resulting white solid was collect by vacuumfiltration and washed with cold ethyl ether to provide the titlecompound (595 mg, 66%). HRMS calculated for C₂₁H₂₄N₂O₅S: 416.1407, found416.1398. Analytical calculation for C₂₁H₂₄N₂O₅S: C, 55.68; H, 5.56; N,6.18; S, 7.08; Cl, 7.83. Found: C, 55.39; H, 5.72; N, 6.15; S, 7.29; Cl,8.17.

EXAMPLE 18 Preparation ofN-hydroxy-1-(methylsulfonyl)-4-(phenoxyphenyl)-sulfonyl]-4-piperidinecarboxamide

Part A: To a solution of the amine hydrochloride salt of Example 6, partB (1.06 g, 2.5 mmol) in dichloromethane (10 mL) were added triethylamine(0.76 mL, 5.5 mmol) and methanesulfonyl chloride (0.23 mL, 3.0 mmol),and the solution was stirred for 18 hours at ambient temperature. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was washed with H₂O andsaturated NaCl and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/hexane) provided the methanesulfonamide as a solid(2.1 g, 58%).

Part B: To a solution of the methanesulfonamide of part A (2.0 g, 4.15mmol) in ethanol (12 mL) and H₂O (12 mL) was added NaOH (1.66 g, 41.5mmol), and the solution was heated to 65 degrees Celsius for 18 hours.The solution was concentrated in vacuo and the remaining aqueoussolution was acidified to a pH of 4. The solution was extracted withethyl acetate and the organic layer was washed with saturated NaCl anddried over magnesium sulfate. Concentration in vacuo provided the acidas a yellow foam (1.46 g, 80%).

Part C: To a solution of the acid of part B (1.46 g, 3.38 mmol) indichloromethane (50 mL) were added triethylamine (1.41 mL, 10.1 mmol),50 percent aqueous hydroxylamine (2.2 mL, 33.8 mmol) and PyBroP (3.16 g,6.76 mmol), and the solution was stirred at ambient temperature for 72hours. The solution was diluted with H₂O and the organic layer wasseparated and washed with saturated NaCl, and then dried over magnesiumsulfate. Reverse phase chromatography (on silica, acetonitrile/H₂O)followed by trituration with ethyl ether provide the title compound as awhite solid (160 mg, 11%). Analytical calculation for C₁₉H₂₂N₂O₇S₂: C,50.21; H, 4.88; N, 6.16; S, 14.11. Found: C, 48.72; H, 5.36; N, 5.61; S,12.81.

EXAMPLE 19 Preparation of4-[[4-(cyclohexylthio)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the sulfone of Example 9, part D (10.1 g, 24.0mmol) in DMF (20 mL) were added K₂CO₃ (5.0 g, 36.0 mmol) andcyclohexylmercaptan (4.4 mL, 36.0 mmol), and the solution was heated at85 degrees Celsius for 6.5 hours. The solution was partitioned betweenethyl acetate and H₂O. The organic layer was washed with saturated NaCland dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as a oil (8.2 g, 67%).

Part B: To a solution of the sulfide (2.32 g, 4.5 mmol) in ethanol (10mL) and THF (10 mL) was added NaOH (1.81 g, 45 mmol) in H₂O (10 mL), andthe solution was heated to 65 degrees Celsius for 18 hours. The solutionwas concentrated in vacuo and the aqueous residue was acidified to a pHvalue of 2. The solution was extracted with dichloromethane and driedover magnesium sulfate. Concentration in vacuo provided the acid as awhite solid (830 mg, 38%).

Part C: To a solution of the acid of part B (2.0 g, 4.0 mmol) indichloromethane (25 mL) were added N-methylmorpholine (1.32 mL, 12.0mmol), PyBroP (2.12 g, 2.12 mmol) and 50 percent aqueous hydroxylamine(2.6 mL, 40 mmol), and the solution was stirred for 18 hours at ambienttemperature. The solution was diluted with H₂O and the layers wereseparated. The organic layer was washed with saturated NaCl and driedover magnesium sulfate. Chromatography (on silica, ethylacetate/methanol) provided the hydroxamate as a white solid (1.4 g,70%).

Part D: Into a solution of the hydroxamate of part C (1.31 g, 2.63 mmol)in ethyl acetate (70 mL) cooled to zero degrees Celsius was bubbled HClgas for 30 minutes. The solution was concentrated in vacuo. Reversephase chromatography (on silica, acetonitrile/H₂O(HCl)) provided thetitle compound as a white solid (378 mg, 33%). Analytical calculationfor C₁₈H₂₆N₂O₄S₂: C, 49.70; H, 6.26; N, 6.44; S, 14.74; Cl, 8.15. Found:C, 48.99; H, 6.34; N, 6.24; S, 14.66; Cl, 8.56.

EXAMPLE 20 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-phenyl-1-piperazinyl)phenyl]sulfonyl]-2H-pyran-4-carboxamide,dihydrochloride

Part A: To a solution of the tetrahydropyran compound of Example 11,part C (1.96 g, 6.5 mmol) in DMSO (20 mL) were added Cs₂CO₃ (4.9 g, 15mmol) and 4-phenylpiperazine (1.1 mL, 7.15 mmol), and the solution washeated to 90 degrees Celsius for 45 minutes. The solution was quenchedby the addition of H₂O and was extracted with ethyl acetate. The organiclayer was washed with 5 percent aqueous KHSO₄, saturated NaHCO₃ andsaturated NaCl and dried over magnesium sulfate. Concentration in vacuoprovided the amine as a beige solid (1.7 g, 59%).

Part B: To a solution of the amine of part A (1.5 g, 3.38 mmol) in THF(20 mL) was added potassium trimethylsilanolate (480 mg, 3.72 mmol), andthe solution was stirred at ambient temperature for 22 hours.Concentration in vacuo provided the crude acid salt to be used withoutpurification in the next step.

Part C: To a solution of the acid salt of part B (1.58 g, 3.38 mmol) indichloromethane (10 mL) and DMF (3 mL) were added PyBroP (1.89 g, 4.06mmol), N-methylmorpholine (1.1 mL, 10.1 mmol) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (435 mg, 3.72 mmol), and thesolution was stirred at ambient temperature for 18 hours. The solutionwas concentrated in vacuo and the residue was partitioned between ethylacetate and H₂O and the organic layer was washed with H₂O and saturatedNaCl, and then dried over magnesium sulfate. Chromatography (on silica,dichloromethane/methanol) provided the protected hydroxamate as a whitefoam (1.7 g, 95% over two steps).

Part D: To a solution of the protected hydroxamate of part C (1.28 g,2.4 mmol) in dioxane (5 mL) and methanol (5 mL) was added 4N HCl indioxane (5 mL), and the solution was stirred for 2 hours at ambienttemperature. The solution was poured into ethyl ether and the resultingprecipitate was collected by vacuum filtration to provide the titlecompound as a white solid (900 mg, 73%). MS (CI) MH⁺ calculated forC₂₂H₂₇N₃O₅S: 446, found 446.

EXAMPLE 21 Preparation of4-[[4-(cyclohexylthio)phenyl]sulfonyl]-1-cyclopropyl)-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the sulfone of Example 9, part D (10.1 g, 24.0mmol) in DMF (20 mL) were added K₂CO₃ (5.0 g, 36.0 mmol) andcyclohexylmercaptan (4.4 mL, 36.0 mmol), and the solution was heated at85 degrees Celsius for 6.5 hours. The solution was partitioned betweenethyl acetate and H₂O. The organic layer was washed with saturated NaCland dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as a oil (8.2 g, 67%).

Part B: HCl gas was bubbled for 30 minutes into a solution of thesulfide of part B (8.2 g, 17.0 mmol) in ethyl acetate (100 mL) cooled tozero degrees Celsius. The solution was concentrated in vacuo to providethe amine as a white solid (5.99 g, 79%). MS (CI) MH⁺ calculated forC₂₀H₂₉NO₄S: 412, found 412.

Part C: To a solution of the amine of part B (2.24 g, 5.0 mmol) inmethanol (20 mL) was added acetic acid (2.86 mL, 50 mmol) followed by(1-ethoxycyclopropyl)oxytrimethylsilane (6.03 mL, 30 mmol) and sodiumborohydride (1.41 g, 22.5 mmol), and the solution was refluxed for 18hours. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate and washed with 1N NaOH, H₂O and saturatedNaCl and dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the cyclopropyl amine as a white solid (1.97 g,87%).

Part D: To a solution of the cyclopropyl amine of part C (1.9 g, 4.2mmol) in ethanol (10 mL) and THF (10 mL) was added NaOH (1.68 g, 42.0mmol) in H₂O (10 mL) and the solution was heated at sixty-eight degreesCelsius for 18 hours. The solution was concentrated in vacuo and theaqueous residue was acidified to a pH value of 2. The resulting solidwas collected and washed with ethyl ether to provide the acid as a whitesolid (1.61 g, 81%). HRMS calculated for C₂₁H₂₉NO₄S₂: 424.1616, found424.1615.

Part E: To a solution of the acid of part D (1.61 g, 3.0 mmol) indichloromethane (30 mL) were added N-methylmorpholine (1.0 g, 9.0 mmol),PyBroP (1.54 g, 3.3 mmol) and 50 percent aqueous hydroxylamine (2.0 mL,30 mmol), and the solution was stirred for 18 hours at ambienttemperature. The solution was concentrated in vacuo. The residue waspartitioned between ethyl acetate and H₂O, the organic layer washed withH₂O and saturated NaCl, and then dried over magnesium sulfate.Filtration through a silica pad (ethyl acetate/methanol) gave thehydroxamate as a white solid (1.07 g, 80%).

Part F: To a solution of the hydroxamate of part F (1.07 g, 2.4 mmol) incold methanol (2 mL) was added acetyl chloride (0.27 mL, 3.6 mmol), andthe solution was stirred for 30 minutes. The solution was concentratedin vacuo. Reverse phase chromatography (acetonitrile/H₂O(HCl)) providedthe title compound as a white solid (245 mg, 21%).

EXAMPLE 22 Preparation of4-[[4-[(4-fluorophenyl)thio]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the sulfone of Example 9, part D (6.0 g, 14.4mmol) in DMF (30 mL) were added potassium carbonate (2.39 mg, 17.3 mmol)and 4-fluorothiophenol (3.0 mL, 28.1 mmol), and the solution was stirredat ambient temperature for 18 hours. The solution was diluted with ethylacetate and washed with 1N NaOH and saturated NaCl, and then dried overmagnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the sulfide as a solid (6.6 g, 87%).

Part B: To a solution of the sulfide of part A (6.6 g, 12.6 mmol) inethanol (90 mL) and H₂O (20 mL) was added sodium hydroxide (5.04 g, 126mmol), and the solution was heated at 70 degrees Celsius for 18 hours.The mixture was acidified to a pH value of 4 and the solution wasextracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/ethanol) provided the solid acid (4.8 g, 79%).

Part C: To a solution of the acid of part B (4.8 g, 10.0 mmol) in DMF(30 mL) was added 4-methylmorpholine (3.03 g, 30.0 mmol) followed byO-tetrahydro-2H-pyran-2-yl-hydroxylamine (7.45 g, 50.0 mmol) and PyBroP(5.59 g, 12.0 mmol), and the solution was stirred for 18 hours atambient temperature. The solution was concentrated in vacuo. The residuewas dissolved into ethyl acetate and washed with H₂O and saturated NaCl,and then dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the protected hydroxamate as a white solid (4.0g, 67%).

Part D: HCl gas was bubbled for 5 minutes into a solution of theprotected hydroxamate of part D (4.0 g, 6.7 mmol) in ethyl acetate (120mL) followed by stirring at ambient temperature for 1.5 hours. Theresulting solid was collected by vacuum filtration to provide the titlecompound as a white solid (1.90 g, 64%). MS (CI) MH⁺ calculated forC₁₈H₁₉N₂O₄S₂F: 411, found 411.

EXAMPLE 23 Preparation ofN-hydroxy-4-[[4-[4-(1H-imidazol-1-yl)phenoxy]phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,dihydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 9, partF (3.00 g, 8.49 mmol) in DMF (13 mL) were added K₂CO₃ (2.35 g, 17.0mmol) and 4-(imidazol-1-yl)phenol (2.72 g, 17.0 mmol), and the solutionwas heated to 85 degrees Celsius for 64 hours. The solution wasconcentrated and the residue was partitioned between ethyl acetate andH₂O. The organic layer was washed with H₂O and saturated NaCl and driedover magnesium sulfate. Chromatography (on silica, chloroform/methanol)provided the ethyl ester as a white foam (2.36 g, 56%).

Part B: To a solution of the ethyl ester of part A (2.36 g, 5.33 mmol)in ethanol (2.8 mL) and H₂O (4.6 mL) was added KOH (1.80 g, 32.1 mmol),and the solution was heated to 100 degrees Celsius for 4.5 hours. Thesolution was acidified to a pH value of 1 with concentrated HCl solutionand then concentrated to provide the acid as a tan solid that was usedwithout additional purification (2.87 g).

Part C: To a solution of the acid of part B (2.87 g, 5.33 mmol) inacetonitrile (24 mL) were added O-tetrahydro-2H-pyran-2-yl-hydroxylamine(870 mg, 7.45 mmol), EDC (1.43 g, 7.45 mmol) and N-methylmorpholine(1.21 mL, 11.0 mmol) and the solution was stirred for 18 hours atambient temperature. The solution was concentrated and the residue wasdiluted with H₂O and extracted with ethyl acetate. The organic layer waswashed with H₂O and saturated NaCl and dried over magnesium sulfate.Chromatography (chloroform, methanol) provided the protectedhydroxylamine as a white solid (1.62 g, 53%).

Part D: To a solution of the protected hydroxylamine of part C (1.60 g,2.63 mmol) in methanol (23 mL) was added acetyl chloride (0.61 mL, 8.52mmol), and the solution was stirred for 1 hour. The solution wasconcentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the title compound as a white solid (975 mg,62%). MS (CI) MH⁺ calculated for C₂₄H₂₅N₄O₅S: 481, found 481. Analyticalcalculation for C₂₄H₂₅N₄O₅S2HCl: C, 52.08; H, 4.73; N, 10.12; S, 5.79;Cl, 12.61. Found: C, 51.59; H, 4.84; N, 10.93; S, 5.51; Cl, 11.98.

EXAMPLE 24 Preparation of4-[[4-[(4-fluorophenyl)thiophenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the propargyl amine of Example 9, part F (4.06g, 11.49 mmol) in DMF (20 mL) were added potassium carbonate (3.18 g,22.98 mmol) and 4-fluorothiophenol (2.95 g, 22.98 mmol), and thesolution was stirred for 18 hours at ambient temperature. The solutionwas diluted with ethyl acetate, washed with 1N NaOH and saturated NaCl,and dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as a solid (4.46 g, 84%).

Part B: To a solution of the sulfide of part A (4.46 g, 9.7 mmol) intetrahydropyran (90 mL), H₂O (30 mL) and ethanol (30 mL) was added NaOH(3.86 g, 97.0 mmol), and the solution was heated to 65 degrees Celsiusfor 2 hours. The solution was concentrated in vacuo and the residue wasdissolved into H₂O and acidified to a pH value of 4 with 2N HCl. Theresulting residue was collected by vacuum filtration to provide the acidas a white solid (4.0 g, 95%).

Part C: To a solution of the acid of part B (4.0 g, 9.2 mmol) in DMF (50mL) and 4-methylmorpholine (2.8 g, 27.7 mmol) was addedO-tetrahydro-2H-pyran-2-yl-hydroxylamine (6.88 g, 46.1 mmol) and PyBroP(5.16 g, 11.1 mmol), and the solution was stirred at ambient temperaturefor 18 hours. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate. The solution was washed with H₂O andsaturated NaCl, and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/hexane) provided the protected hydroxamate as awhite solid (2.8 g, 56%).

Part D: HCl gas was bubbled for 10 minutes into a solution of theprotected amine of part C (2.8 g, 5.1 mmol) in ethyl acetate (100 mL),and the solution was then stirred for 1 hour. The solution wasconcentrated in vacuo and the solid recrystallized (ethanol) to providethe title compound as a white solid (1.12 g, 45%). MS (CI) MH⁺calculated for C₂₁H₂₁N₂O₄S₂F: 449, found 449.

EXAMPLE 25 Preparation of4-[[4-[(4-chlorophenyl)thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the tetrahydropyran compound of Example 11,part C (8.0 g, 26.5 mmol) in THF (250 mL) was added potassiumtrimethylsilonate (10.2 g, 79.5 mmol), and the solution was stirred for1.5 hours. The reaction was quenched by the addition of H₂O, acidifiedto a pH value of 2.5, and the solution was extracted with ethyl acetate.The organic layer was washed with saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provide the acid salt as a white solid (5.78 g,76%).

Part B: To a solution of the acid salt of part A (5.4 g, 18.7 mmol) inDMF (35 mL) were added HOBT(3.04 g, 22.5 mmol), N-methylmorpholine (6.2mL, 56.2 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (6.8 g, 58.1mmol) and EDC (5.0 g, 26.2 mmol), and the solution was stirred for 3hours at ambient temperature. The solution was concentrated in vacuo,the residue partitioned between ethyl acetate and H₂O, and the organiclayer was washed with 5 percent aqueous KHSO₄, H₂O, saturated NaHCO₃ andsaturated NaCl, and then dried over Na₂SO₄. Concentration in vacuoprovided the protected hydroxamate as a white solid (6.34 g, 87%).

Part C: To a solution of p-chlorothiophenol (2.71 g, 18.7 mmol) in DMF(10 mL) was added K₂CO₃ (2.6 g, 18.7 mmol) followed by the protectedhydroxamate of part B (2.9 g, 7.5 mmol) and the solution was heated at75 degrees Celsius for 5 hours. The solution was concentrated in vacuo,the residue partitioned between ethyl acetate and H₂O, the organic layerwas washed with saturated NaCl, and dried over Na₂SO₄. Chromatography(on silica, ethyl acetate/hexane/methanol) provided the sulfide as awhite foam (3.56 g, 93%). MS (CI) MH⁺ calculated for C₂₃H₂₆ClNO₆S₂: 512,found 512.

Part D: To a solution of the sulfide of part C (3.5 g, 6.8 mmol) indioxane (10 mL) was added 4N HCl in dioxane (10 mL). After 10 minutes ofstirring, methanol (10 mL) was added with continued stirring for onehour. The solution was concentrated in vacuo. Recrystallization(acetone/hexane) provided the title compound as a white solid (2.4 g,83%). MS (CI) MH⁺ calculated for C₁₈H₁₈ClNO₅S: 428, found 428.

EXAMPLE 26 Preparation ofTetrahydro-N-hydroxy-4-[[4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]-phenyl]-sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a solution of the protected hydroxamate of Example 25, part B(2.9 g, 7.5 mmol) in DMF (10 mL) was added 4-(1,2,4-triazol-1-yl)phenol(2.47 g, 15 mmol) in DMF (5 mL) followed by Cs₂CO₃ (7.33 g, 22.5 mmol),and the solution was heated at 95 degrees Celsius for 5 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane/methanol) provided the phenol as a white solid (3.16 g,80%).

Part B: To a solution of the phenol of part A (2.8 g, 5.3 mmol) indioxane (10 mL) was added 4N HCl in dioxane (10 mL). After 5 minutes ofstirring, methanol (10 mL) was added and stirring was continued for 1hour. The solution was then poured into ethyl ether, and the resultingprecipitate was collected by vacuum filtration to provide the titlecompound as a white solid (2.44 g, 96%). MS (CI) MH⁺ calculated forC₂₀H₂₀N₄O₆S: 445, found 445.

EXAMPLE 27 Preparation of1-cyclopropyl-4-[[4-[(4-fluorophenyl)thiol]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: HCl gas was bubbled for 7 minutes into a solution of the sulfideof Example 9, part D (7.06 g, 13.5 mmol) in ethyl acetate (150 mL), andthe solution was stirred for 15 minutes at zero degrees Celsius. Thesolution was concentrated in vacuo to provide the amine as a white solid(6.43 g, quantitative yield).

Part B: To a solution of the amine of part A (6.4 g, 13.9 mmol) inmethanol (65 mL) was added acetic acid (7.96 mL, 139 mmol) and a scoopof 3A molecular sieves. To this mixture was added(1-ethoxycyclopropyl)-oxytrimethylsilane (16.8 mL, 84 mmol) followed bysodium cyanoborohydride (3.9 g, 62 mmol). The solution was heated toreflux for 6 hours. The solution was filtered and the filtrate wasconcentrated in vacuo. The residue was dissolved into ethyl acetate,washed with H₂O, 2N NaOH and saturated NaCl, and dried over magnesiumsulfate. Filtration through a pad of silica (hexane/ethyl acetate)provided the cyclopropyl amine as a white solid (6.49 g, quantitativeyield).

Part C: To a solution of the cyclopropyl amine of part B (6.4 g, 13.8mmol) in ethanol (30 mL) and THF (30 mL) was added NaOH (5.5 g, 138mmol) in H₂O (23 mL), and the solution was heated to 65 degrees Celsiusfor 12 hours. The solution was concentrated in vacuo and the aqueouslayer was acidified to a pH value of 2 with 2N HCl. The resulting whiteprecipitate was collected by filtration to provide the acid as a whitesolid (5.2 g, 87%). MS (CI) MH⁺ calculated for C₂₁H₂₂NO₄S₂F: 436, found436.

Part D: To a solution of the acid of part C (2.27 g, 5.2 mmol) in DMF(60 mL) was added HOBT (845 mg, 6.2 mmol) followed by N-methylmorpholine(1.71 mL, 15.6 mmol), EDC (1.40 g, 7.28 mmol) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (913 mg, 7.8 mmol), and thesolution was stirred at ambient temperature for 72 hours. The solutionwas concentrated in vacuo, the residue was dissolved intodichloromethane and washed with H₂O and saturated NaCl, and then driedover magnesium sulfate. Chromatography (on silica, hexane/ethyl acetate)provided the protected hydroxamate as a white solid (1.95 g, 70%).

Part E: To a solution of the protected hydroxamate of part D (3.2 g, 6.0mmol) in cold methanol (100 mL) was added acetyl chloride (1.3 mL, 18.0mmol) in methanol (30 mL), and the solution was stirred at ambienttemperature for 4 hours. The solution was concentrated in vacuo and theresidue was triturated with ethyl ether to provide the title compound asa white solid (2.86 g, 98%). MS (CI) MH⁺ calculated for C₂₁H₂₃N₂O₄S₂F:451, found 451. Analytical calculation for C₂₁H₂₃N₂O₄S₂F0.25H₂OHCl: C,51.32; H, 5.02; N, 5.70; S, 13.05; Cl, 7.21. Found: C, 50.99; H, 4.91;N, 5.65; S, 13.16; Cl, 7.83.

EXAMPLE 28 Preparation ofN-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propenyl)-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 9, partE (4.78 g, 10.8 mmol) in DMF (25 mL) were added K₂CO₃ (2.98 g, 21.6mmol) and allyl bromide (0.935 mL, 10.8 mmol), and the solution wasstirred for 5 hours at ambient temperature. The solution was partitionedbetween ethyl acetate and H₂O, and the organic layer was washed with H₂Oand saturated NaCl, and dried over magnesium sulfate. Filtration througha pad of silica (hexane/ethyl acetate) provided the allyl amine as anoil (4.80 g, quantitative yield).

Part D: To a solution of the allyl amine of part A (4.8 g, 10.8 mmol) inethanol (25 mL) and THF (25 mL) was added NaOH (4.3 g, 108 mmol) in H₂O(20 mL), and the solution was heated to 65 degrees Celsius for 18 hours.The solution was concentrated in vacuo and diluted with H₂O The aqueoussolution was acidified to a pH value of 3. The resulting precipitate wascollected by vacuum filtration to provide the acid as a beige solid (4.1g, 84%). MS (CI) MH⁺ calculated for C₂₁H₂₃NO₄S₂: 418, found 418.

Part C: To a solution of the acid of part B (4.1 g, 9.0 mmol) in DMF (90mL) was added HOBT (1.46 g, 11.0 mmol) followed by N-methylmorpholine(2.97 mL, 2.7 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.58 g,13.5 mmol) and EDC (2.42 g, 13.0 mmol), and the solution was stirred for72 hours. The solution was concentrated in vacuo. The residue wasdissolved in dichloromethane and washed with H₂O and saturated NaCl, andthen dried over magnesium sulfate. Chromatography (on silica, ethylacetate/methanol) provided the protected hydroxylamine as a white solid(4.11 g, 88%).

Part D: To a solution of the protected hydroxylamine of part C (4.11 g,8.0 mmol) in ethyl acetate (100 mL) cooled to zero degrees Celsius wasadded acetyl chloride (1.71 mL, 24.0 mmol), and the solution was stirredfor 4 hours at ambient temperature. The solution was concentrated invacuo and trituration with ethyl ether provided the title compound as awhite solid (3.53 g, 95%). Analytical calculation forC₂₁H₂₄N₂O₄S₂HCl0.5H₂O: C, 52.76; H, 5.48; N, 5.86; S, 13.42; Cl, 7.42.Found: C, 52.57; H, 5.69; N, 6.29; S, 12.59; Cl, 7.80.

EXAMPLE 29 Preparation of1-(cyclopropylmethyl)-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the amine hydrochloride salt of Example 6, partE (2.13 g, 5.0 mmol) in DMF (10 mL) were added K₂CO₃ (1.4 g, 10.0 mmol)and bromomethylcyclopropane (0.48 mL, 5.0 mmol), and the solution wasstirred for 18 hours at ambient temperature. The solution waspartitioned between ethyl acetate and H₂O, the organic layer was washedwith H₂O and saturated NaCl, and then dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexane) provided the solidcyclopropylmethylamine (2.09 g, 91%).

Part B: To a solution of the cyclopropylmethylamine of part A (2.0 g,4.4 mmol) in ethanol (12 mL) and THF (12 mL) was added NaOH (1.75 g, 44mmol) in H₂O (10 mL), and the solution was heated to 65 degrees Celsiusfor 18 hours. The solution was concentrated in vacuo and the aqueousresidue was acidified to a pH value of 5. The resulting precipitate wascollected by vacuum filtration to provide the acid as a white solid(1.58 g, 79%). HRMS calculated for C₂₂H₂₅NO₅S: 414.1375, found 414.1334.

Part C: To a solution of the acid of part B (1.58 g, 3.5 mmol) indichloromethane (50 mL) was added triethylamine (1.46 mL, 10.5 mmol)followed by 50 percent aqueous hydroxylamine (2.3 mL, 35 mmol) andPyBroP (3.26 g, 6.99 mmol), and the solution was stirred at ambienttemperature for 72 hours. The solution was washed with H₂O and saturatedNaCl, and dried over magnesium sulfate. Reverse phase chromatography (onsilica, acetonitrile/H₂O) provided the hydroxamate as a white solid (3.2g, quantitative yield).

Part D: To a solution of the hydroxamate of part C (1.5 g, 3.5 mmol) incold methanol (20 mL) was added acetyl chloride (0.25 mL, 3.5 mmol) inmethanol (5 mL) and the solution was stirred at zero degrees Celsius for15 minutes. After the solution had stirred for an additional 30 minutesat ambient temperature, it was concentrated in vacuo. Trituration withethyl ether provided the title compound as a white solid (229 mg, 7%).

EXAMPLE 30 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[(4-phenoxyphenyl)sulfonyl]-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the amine HCl salt of part E, Example 6 (2.5 g,5.87 mmol) and K₂CO₃ (1.6 g, 11.57 mmol) in N,N-dimethylformamide (25mL) was added 2-bromoethyl methyl ether (0.66 mL, 7.0 mmol) and thenstirred at ambient temperature for 18 hours. Then N,N-dimethylformamidewas evaporated under high vacuum and residue was diluted with ethylacetate. The organic layer was washed with water and dried over Mg₂SO₄.Concentration in vacuo provided the methoxyl ethyl amine as light yellowgel (2.63 g, quantitative yield).

Part B: To a solution of the methoxyl ethyl amine of part A (2.63 g,5.87 mmol) in tetrahydrofuran (18 mL) and ethanol (18 mL) was added NaOH(2.1 g, 5.25 mmol) in water (6 mL). The solution was heated to refluxfor 12 hours. The solution was concentrated in vacuo and diluted withwater. The aqueous layer was extracted with ether (2×100 mL) and wasacidified to pH=2. Vacuum filtration of the resulting precipitationprovided the acid as a white solid (2.4 g, quantitative yield).

Part C: To a solution of the acid of part B (2.0 g, 4.33 mmol), alsocontaining N-methyl morpholine (1.8 mL, 16.4 mmol), andO-tetrahydro-2H-pyran-yl-hydroxylamine (0.767 g, 6.44 mmol) inN,N-dimethylformamide (20 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.1 g,16.2 mmol), and solution was stirred at ambient temperature for 20hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed with H₂Oand dried over Mg₂SO₄. Concentration in vacuo provided the amide as offwhite foam (1.60 g, 71.1%).

Part D: To a solution of the amide of part C (1.58 g, 3.05 mmol) inmethanol (20 mL) cooled to zero degrees Celsius was added acetylchloride (0.65 mL, 9.15 mmol) and the resulting solution was stirred atthe same temperature for 3 hours. The solution was concentrated andreverse phase chromatography (on C-18 silica, acetonitrile/H₂O with0.01% HCl) provided hydroxamate HCl salt as a white solid (0.65 g,45.5%). Analytical calculation for C₂₁H₂₆N₂O₆S.HCl.0.75H₂O: C, 52.06; H,5.93; N, 5.78; S, 6.62. Found: C, 51.94; H, 5.67; N, 5.91; S, 6.66. HSMScalculated for C₂₁H₂₆N₂O₆S: 435.1590, found 435.1571.

EXAMPLE 31 Preparation ofN-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(1-pyrrolidinylacetyl)-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the sulfone of part D, Example 6 (2.75 g,5.6mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added NaOH(2.25 g, 56 mmol) in H₂O (20 mL), and the solution was heated to 70degrees Celsius for 20 hours. The solution was concentrated in vacuo andthe dry residue was dissolved in H₂O. The aqueous layer was extractedwith ether and was acidified to pH=2 followed by the extraction withethyl acetate. The combined organic layers were washed again with H₂Oand dried over Mg₂SO₄. Concentration in vacuo provided the BOC-acid aswhite foam (2.3 g, 88.8%).

Part B: To a solution of BOC-acid of part A (2.3 g, 4.98 mmol) indichloromethane (6 mL) was added trifluroacetic acid (6 mL, 77.8 mmol),and the resulting solution was stirred at ambient temperature for 1hour. Concentration in vacuo provided the amine as white foam (2.44 g,quantitative yield).

Part C: To the solution of the amine of part B (2.4 g, 4.9 mmol) andtriethylamine (3.5 mL, 24.4 mmol) in acetone (15 mL) and H₂O (15 mL) wasadded chloroacetyl chloride (1.2 mL, 14.7 mmol), and solution wasstirred at ambient temperature for 20 hours. Then acetone was evaporatedand aqueous layer was acidified to pH=2. The aqueous layer was extractedwith ethyl acetate and the organic layer was washed with water and driedover Mg₂SO₄. Concentration in vacuo provided the chloroacetyl amide aslight yellow gel (2.78 g, quantitative yield).

Part D: To the solution of the chloroacetyl amide of part C (2.78 g,4.93 mmol) and K₂CO₃ (5 g, 36 mmol) in N,N-dimethylformamide (20 mL) wasadded pyrolidine (3 mL, 36 mmol). The solution was then stirred atambient temperature for 18 hours. Then N,N-dimethylformamide wasevaporated under high vacuum and reverse phase chromatography (on C-18silica, acetonitrile/H₂O with 0.01% HCl) provided pyrolidine acetylamide (0.25 g, 10.7%).

Part E: To a solution of the pyrolidine acetyl amide of part D (0.25 g,0.53 mmol), also containing N-methyl morpholine (0.14 mL, 1.27 mmol),1-hydroxybenzotriazole (0.17 g, 1.2 mmol) andO-tetrahydro-2H-pyran-yl-hydroxylamine (0.15 g, 1.26 mmol) inN,N-dimethylformamide (4 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.23 g,1.2 mmol). The solution was then stirred at ambient temperature for 18hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated NaHCO₃, H₂O and dried over Mg₂SO₄. Concentration in vacuoprovided the THP amide as white foam (0.25 g, 83.3%).

Part F: To a solution of the amide of part E (0.25 g, 0.437 mmol) inmethanol (4 mL) cooled to zero degrees Celsius was added acetyl chloride(0.075 mL, 1.05 mmol), and the resulting solution was stirred at ambienttemperature for 2.5 hours. The solution was concentrated and reversephase chromatography (on C-18 silica, acetonitrile/H₂O with 0.01% HCl)provided hydroxamate HCl salt as a white solid (80 mg, 29%). Analyticalcalculation for C₂₄H₂₉N₃O₆S.HCl.0.9H₂O: C, 53.36; H, 5.98; N, 7.78.Found: C, 53.61; H, 5.71; N, 7.94. HSMS calculated for C₂₄H₂₉N₃O₆S:488.1855, found 488.1835.

EXAMPLE 32 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

Part A: A solution of 4-flurothiophenol (50.29 g, 0.39 mmol) indimethylsulfoxide (500 mL) was heated to 65 degrees Celsius for 5 hours.The solution was cooled to ambient temperature and poured intovigorously stirred ice water. The precipitate was filtered and washedtwice with water. Drying under high vacuum provided the disulfide as ayellow oil (34.39 g, 68.9%) at ambient temperature.

Part B: A solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) intetrahydrofuran (5 mL) was added dropwise over 20 minutes to a solutionof ethyl isonipecotate (15.7 g, 0.1 mol) in tetrahydrofuran (100 mL).The resulting solution was stirred overnight (about eighteen hours) atambient temperature and concentrated in vacuo to yield a light oil. Theoil was filtered through silica gel (ethyl acetate/hexane) andconcentrated in vacuo to give the BOC-piperidine compound as a clear,colorless oil (26.2 g, quantitative yield).

Part C: To a solution of BOC-piperidine compound of part B (15.96 g, 62mmol) in tetrahydrofuran (300 mL), cooled to minus forty degreesCelsius, was added lithium diisopropylamide (41.33 mL, 74 mmol). Thesolution was then stirred at minus forty degrees C. for one hour andzero degree C for one-half hour. Then the solution was cooled to minusforty degrees Celsius again and the disulfide of part A (15.77 g, 62mmol) in tetrahydrofuran (20 mL) was added. The resulting solution asstirred at ambient temperature for 18 hours. The solution was dilutedwith H₂O and extracted with ethyl acetate. The organic layer was washedwith H₂O and saturated NaCl and dried over MgSO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the sulfide as an oil (18 g,75%).

Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) indichloromethane (500 mL) cooled to zero degrees Celsius, was addedm-chloroperbenzoic acid (18.5 g, 107 mmol). After 2 hours, the solutionwas diluted with dichloromethane and washed with 1N KOH, H₂O and driedover MgSO₄. Concentration in vacuo provided the sulfone as a solid (21g, quantitative yield).

Part E: To a solution of sulfone (40 g, 96 mmol) of part D and powderedK₂CO₃ (26 g, 188 mmol) in N,N-dimethylformamide (200 mL) cooled to zerodegrees Celsius was added thiolphenol (19.8 mL, 192 mmol), and theresulting composition was then stirred at ambient temperature for 36hours. That solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed with H₂Oand dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided phenyl thiophenyl Boc-sulfone as white solid(44.34 g, 91%).

Part F: To a solution of phenyl thiophenyl Boc-sulfone of part E (8.6 g,17 mmol) in dichloromethane (30 mL) cooled to zero degrees Celsius wasadded trifluroacetic acid (TFA; 30 mL), and the resulting solution wasstirred at ambient temperature for 2 hours. Concentration in vacuoprovided the amine TFA salt as a light yellow gel (8.7 g, quantitativeyield).

Part G: To a solution of amine TFA salt of part F (6 g, 11.9 mmol) wasadded acetic acid (6.8 mL, 119 mmol). After 5 minutes stirring atambient temperature, (1-ethoxylcyclopropyl)oxytriomethylsilane (14.3 mL,71.4 mmol) was added followed 5 minutes later by the addition of sodiumcyanoboran hydrate (3.35 g, 53.55 mmol). Then the solution was heated toreflux for 18 hours. Methanol was evaporated and residue was dissolvedin ethyl acetate. The organic layer was washed with 1N NaOH, H₂O anddried over Mg₂SO₄. Concentration in vacuo gave the cyclopropylamine asan off-white powder (4.9 g, 92.6%).

Part H: To a solution of the cyclopropylamine of part G (4.88 g, 10.95mmol) in tetrahydrofuran (12.5 mL) and ethanol (12.5 mL) was added NaOH(4.3 g, 100 mmol) in water (25 mL). The solution was then heated to50-55 degrees Celsius for 12 hours and was stirred at ambienttemperature for 18 hours. Solution was acidified to pH=2 andconcentration in vacuo provided the acid as white solid together withNaCl in the mixture. To a solution of this mixture in acetonitrile (50mL) were added O-tetrahydropyronylamine (1.95 g, 16.3 mmol),N-methylmorpholine (2.4 mL, 21.9 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.14 g,16.3 mmol) in sequence. The solution was then stirred at ambienttemperature for 18 hours. The solution was concentrated in vacuo and theresidue was dissolved in ethyl acetate. The organic layer was washedwith H₂O and dried over Mg₂SO₄. Concentration in vacuo provided thetetrehyrdopyronyl (THP) amide as white solid (3.0 g, 53.1%).

Part I: To a solution of the THP amide of part H (3 g, 5.8 mmol) inmethanol (45 mL) cooled to zero degrees Celsius was added acetylchloride (1.5 mL, 21.1 mmol), and the solution was stirred at ambienttemperature for 2.5 hours. Vacuum filtration of the precipitate providedhydroxamate HCl salt as a white solid (1.844 g, 68.3). Analyticalcalculation for C₂₁H₂₄N₂O₄S₂.HCl: C, 53.78; H, 5.37; N, 5.97; S, 13.67.Found: C, 53.40; H, 5.26; N, 5.95; S, 13.68.

EXAMPLE 33 Preparation ofN-hydroxy-1-methyl-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of amine TFA salt of part F, Example 32 (2.67 g,5.14 mmol) and 37% formaldehyde in aqueous solution (2.0 mL, 25.7 mmol)in methanol (20 mL) was added borane pyridine (2.6 mL, 25.7 mmol) atambient temperature. The solution was then stirred at ambienttemperature for 18 hours. The solution was acidified to destroy excessreagent. Methanol was evaporated and the residue was partitioned betweenNaHCO₃ aqueous solution and ethyl acetate. The NaHCO₃ aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith H₂O and dried over Mg₂SO₄. Concentration in vacuo gave the methylamine as off white foam (1.6 g, 76%).

Part B: To a solution of the methyl amine S of part A (1.63 g, 3.88mmol) in ethanol (20 mL) was added KOH (1.31 g, 23.2 mmol) in water (4mL), and the resulting solution was heated to 50 degrees Celsius for 9hours, 70 degree Celsius for 4 hours and stirred at ambient temperaturefor 18 hours. The solution was acidified and concentrated in vacuoproviding the acid as white solid together with NaCl in the mixture. Toa solution of this mixture in N,N-dimethylformamide (50 mL) were addedO-tetrahydropyronylamine (0.92 g, 7.76 mmol), N-methylmorpholine (1.05mL, 7.76 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (1.5 g, 7.76 mmol) in sequence. The solution was stirredat ambient temperature for 72 hours. The solution was concentrated inhigh vacuum and the residue was dissolved in ethyl acetate. The organiclayer was washed with saturated NaHCO₃, H₂O and dried over Mg₂SO₄.Concentration in vacuo and chromatography (silica,dichloromethane/methanol) provided the THP amide as white solid (0.46 g,24.2%).

Part C: To a solution of the THP amide of part B (0.22 g, 0.45 mmol) inmethanol (5 mL) cooled to zero degrees Celsius was added acetyl chloride(0.096 mL, 13.5 mmol), and the resulting solution was stirred at ambienttemperature for 3 hours. The solution was concentrated in vacuo andreverse phase chromatography (on C-18 silica, acetonitrile/H₂O with0.01% HCl) provided hydroxamate HCl salt as a white solid (0.12 g,60.6%). HSMS calculated for C₁₉H₂₂N₂O₄S₂: 407.1099, found 407.1105.

EXAMPLE 34 Preparation ofN-hydroxy-1-(1-methylethyl)-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: Into a solution of BOC-sulfone of part E, Example 32 (11.19 g,22.12 mmol) in ethyl acetate (150 mL) cooled to zero degrees Celsius wasbubbled HCl gas for 20 minutes. The solution was stirred at the sametemperature for another 40 minutes. Concentration in vacuo and titrationwith ether provided the amine HCl salt (9.88 g, quantitative yield).

Part B: To a solution of amine HCl salt of part A (4.7 g, 10.6 mmol),triethylamine (2.0 mL, 14.4 mmol) and acetone (2.0 mL, 27.2 mmol) indichloromethane (100 mL) were added sodium triacetoxylborohydride (5.7g, 26.9 mmol) followed by acetic acid (1.5 mL, 26.9 mmol) at ambienttemperature. The solution was stirred for 18 hours and then partitionedin 1N NaOH and ether. The aqueous layer was extracted with ether andcombined organic layers were washed with 1N NaOH, H₂O and dried overMg₂SO₄. Concentration in vacuo gave the isopropyl amine as white foam(4.58 g, 96.2%).

Part C: To a solution of the isopropyl amine of part B (4.58 g, 10.2mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added NaOH (2.1g, 5.25 mmol) in water (20 mL). The solution was heated to 60 degreesCelsius for 13.5 hours, then stirred at ambient temperature for 18hours. The solution was acidified and concentrated in vacuo providingthe acid as white solid together with NaCl in the mixture. To a solutionof this mixture in N,N-dimethylformamide (75 mL) were added1-hydroxybenzotriazole (1.94 g, 14.4 mmol), O-tetrahydropyronylamine(1.8 g, 15.1 mmol), N-methylmorpholine (3.37 mL, 30.7 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.74 g,14.3 mmol) in sequence. The solution was stirred at ambient temperaturefor 48 hours. The solution was concentrated in high vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith saturated NaHCO₃, H₂O and dried over Mg₂SO₄. Concentration in vacuoand chromatography (silica, dichloromethane/methanol) provided the THPamide as white solid (3.78 g, 71.3%).

Part D: To a solution of the THP amide of part C (1.15 g, 2.2 mmol) inmethanol (20 mL) was added acetyl chloride (0.096 mL, 13.5 mmol), andthe resulting solution was stirred at ambient temperature for 2.5 hours.The solution was concentrated in vacuo and reverse phase chromatography(on C-18 silica, acetonitrile/H₂O with 0.01% HCl) provided hydroxamateHCl salt as a white solid (0.69 g, 66.3%). Analytical calculation forC₂₁H₂₆N₂O₄S₂.HCl.H₂O: C, 51.58; H, 5.98; N, 5.73; S, 13.11. Found: C,51.76; H, 5.47; N, 5.72; S, 12.68.

EXAMPLE 35 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To the solution of the amine HCl salt of part A, Example 34 (4.3g, 9.43 mmol) and K₂CO₃ (2.62 g, 19.0 mmol) in N,N-dimethylformamide (40mL) was added 2-bromoethyl methyl ether (1.9 mL, 20.2 mmol). Thesolution was stirred at ambient temperature for 48 hours. ThenN,N-dimethylformamide was evaporated under high vacuum and the residuewas diluted with ethyl acetate. The organic layer was washed with waterand dried over Mg₂SO₄. Concentration in vacuo provided the methoxylethyl amine as white foam (4.26 g, 95.3%).

Part B: To a solution of the methoxyl ethyl amine of part A (4.26 g, 9.2mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was added NaOH (3.7g, 92.5 mmol) in water (9 mL). The solution resulting was heated to 60degrees Celsius for 12 hours and stirred at ambient temperature for 18hours. The solution was concentrated in vacuo and diluted with water.The aqueous layer was extracted with ether (2×100 mL) and was acidifiedto pH=2. Vacuum filtration of the resulting precipitate provided theacid as a while solid (3.5 g, 87.5%).

Part C: To a solution of the acid of part L (3.4 g, 7.8 mmol), alsocontaining N-methyl morpholine (2.6 mL, 23.4 mmol),1-hydroxybenzotriazole (3.16 g, 23.4 mmol), andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.85 g, 15.5 mmol) inN,N-dimethylformamide (20 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.47 g,23.4 mmol). The solution was stirred at ambient temperature for 36hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated NaHCO₃, H₂O and dried over Mg₂SO₄. Concentration in vacuoprovided the amide as off white solid (2.98 g, 71.5%).

Part D: To a solution of the amide of part C (2.98 g, 5.6 mmol) inmethanol (40 mL) cooled to zero degrees Celsius was added acetylchloride (1.19 mL, 16.8 mmol), and the resulting solution was stirred atthe ambient temperature for 3 hours. The solution was concentrated andreverse phase chromatography (on C-18 silica, acetonitrile/H₂O with0.01% HCl) provided hydroxamate HCl salt as a white solid (2.29 g,84.6%). Analytical calculation for C₂₁H₂₆N₂O₆S.HCl.0.9H₂O: C, 50.12; H,5.77; N, 5.57; S, 12.74. Found: C, 50.41; H, 5.85; N, 5.73; S, 12.83.

EXAMPLE 36 Preparation of1-acetyl-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the phenyl thiophenyl BOC-sulfone of part E,Example 32 (7 g, 1.29 mmol) in tetrahydrofuran (25 mL) and ethanol (25mL) was added NaOH (5.1 g, 12.9 mmol) in H₂O (50 mL). The solution washeated to reflux for 20 hours. On cooling, the solution was concentratedin vacuo and the dry residue was dissolved in H₂O. The aqueous layer wasextracted with ether and was acidified to pH=2 followed by theextraction with ethyl acetate. The combined organic layers were washedagain with H₂O and dried over Mg₂SO₄. Concentration in vacuo providedthe BOC-acid as white foam (3.9 g, 60%).

Part B: To a solution of BOC-acid of part A (2.3 g, 4.98 mmol) indichloromethane (6 mL) was added trifluroacetic acid (6 mL, 77.8 mmol),and the solution was stirred at ambient temperature for 1 hour.Concentration in vacuo provided the amine as white foam (2.44 g,quantitative yield).

Part C: To a solution of the amine of part B (5.0 g, 12.08 mmol) andtriethylamine (8.7 mL, 60.4 mmol) in acetone (20 mL) and H₂O (20 mL)cooled to zero degrees Celsius was added acetyl chloride (4.6 mL, 36mmol), and the solution was stirred at ambient temperature for 40 hours.The acetone was evaporated and the aqueous layer was acidified to pH=2.The aqueous layer was extracted with ethyl acetate and the combinedorganic layers were washed with water and dried over Mg₂SO₄.Concentration in vacuo provided the acetyl amide as light yellow foam (5g, quantitative yield).

Part D: To a solution of acetyl amide of part C (5 g, 11.9 mmol), alsocontaining N-methyl morpholine (5.3 mL, 47.6 mmol),1-hydroxybenzotriazole (4.8 g, 35.7 mmol) andO-tetrahydro-2H-pyran-yl-hydroxylamine (2.8 g, 23.5 mmol) inN,N-dimethylformamide (50 mL) was added1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.8 g,35.7 mmol), and the solution was stirred at ambient temperature for 20hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated NaHCO₃, KHSO₄, H₂O and dried over Mg₂SO₄. Concentration invacuo provided the THP amide as white foam (6.07 g, 98.2%).

Part E: To a solution of the THP amide of part D (6.07 g, 11.7 mmol) inmethanol (100 mL) cooled to zero degrees Celsius was added acetylchloride (2.5 mL, 35.1 mmol), and the solution was stirred at ambienttemperature for 3 hours. The solution was concentrated andchromatography (on silica, methanol/dichloromethane) providedhydroxamate HCl salt as a white solid (3.3 g, 65%). Analyticalcalculation for C₂₄H₂₉N₃O₆S.HCl.0.9H₂O: C, 53.36; H, 5.98; N, 7.78.Found: C, 53.61; H, 5.71; N, 7.94. HSMS calculated for C₂₄H₂₉N₃O₆S:488.1855, found 488.1835.

EXAMPLE 37 Preparation of1-acetyl-4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of sulfone from Part D, Example 32 (25 g, 67.3mmol) and powdered K₂CO₃ (23.3 g, 16.9 mmol) in N,N-dimethylformamidewas added sesamol (23.24 g, 16.8 mmol) at ambient temperature, andsolution was heated to ninety degrees Celsius for 24 hours. The solutionwas concentrated under high vacuum and the residue was dissolved inethyl acetate. The organic layer was washed with 1N NaOH, H₂O and driedover MgSO₄. Chromatography (on silica, ethyl acetate/hexane) providedsesamol BOC-sulfone as a white foam (33.6 g, 93.6%).

Part B: To a solution of sesamol BOC-sulfone of part E (29.31 g, 54.93mmol) in ethanol (60 mL) and tetrahydrofuran (60 mL) was added NaOH(21.97 g, 544 mmol) from addition funnel over 20 minutes at ambienttemperature. The solution was then heated to sixty degrees Celsius for 9hours, then ambient temperature for 12 hours. The solution wasconcentrated in vacuo and diluted with water. The aqueous layer wasextracted with ether and acidified to pH=2. It was then extracted withethyl acetate and the combined organic layers were washed with H₂O anddried over MgSO₄. Concentration in vacuo provided the acid as whitesolid (25.3, 91%).

Part C: HCl gas was bubbled into a solution of the acid of part F (20.3g, 40.15 mmol) in ethyl acetate cooled to zero degrees Celsius. After1.5 hours, vacuum filtration of white precipitate provided the amine HClsalt as a white solid (16 g, 93.6%). Part D: To the solution of theamine HCl salt of part G (8.1 g, 19.01 mmol) and triethylamine (13.2 mL,95.05 mmol) in acetone (150 mL) and H₂O (150 mL) cooled to zero degreesCelsius was added acetyl chloride (5.4 mL, 76 mmol). The solution wasstirred at ambient temperature for 18 hours. The acetone was evaporatedand aqueous layer was acidified to pH=2. The aqueous layer was extractedwith ethyl acetate and the combined organic layers were washed withwater and dried over Mg₂SO₄. Concentration in vacuo provided the acetylamide as light yellow foam (9.24 g, quantitative yield).

Part E: To the solution of the acetyl amide of part D (9.1 g, 20.33mmol), N-methyl morpholine (6.7 mL, 61 mmol), 1-hydroxybenzotriazole(8.2 g, 60 mmol) and O-tetrahydro-2H-pyran-yl-hydroxylamine (4.85 g, 40mmol) in N,N-dimethylformamide (40 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.65 g,60 mmol). The resulting solution was stirred at ambient temperature for20 hours. The solution was then concentrated under high vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith saturated NaHCO₃, KHSO₄, H₂O and dried over Mg₂SO₄. Concentrationin vacuo and chromatography (on silica, ethyl acetate/hexane) providedthe THP amide as white a foam (10 g, 89.7%).

Part F: To a solution of 4N HCl in dioxane (20 mL) was added a solutionof the amide of part E (5.0 g, 9.1 mmol) in methanol (5 mL) and dioxane(15 mL). That solution was stirred at ambient temperature for 30minutes. Vacuum filtration of the white precipitate provided thehydroxamate HCl salt as a white solid (3.3 g, 65%). Analyticalcalculation for C₂₁H₂₂N₂O₈S.HCl; C, 54.34; H, 5.15; N, 5.49; S, 6.43.Found; C, 54.54; H, 4.79; N, 6.06; S, 6.93. HSMS calculated forC₂₁H₂₂N₂O₈S: 463.1175, found 463.118.

EXAMPLE 38 Preparation of4-[[4-(3,4-dimethoxyphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: HCl gas was bubbled into a solution of the sulfone of part D,Example 32 (10 g, 24 mmol) in ethyl acetate cooled to zero degreesCelsius. After 4 hours, vacuum filtration of the white precipitateprovided the amine HCl salt as a white solid (7.27 g, 86%).

Part B: To a solution of the amine HCl salt of part A (5.98 g, 17 mmol)and powered K₂CO₃ (4.7 g, 34 mmol) in N,N-dimethylformamide (120 mL) wasadded propargyl bromide (2.022 g, 17 mmol) at ambient temperature,followed by stirring for 4 hours. The solution was diluted with ethylacetate and washed with H₂O, saturated NaCl and dried over Mg₂SO₄.Concentration in vacuo and chromatography (on silica, ethylacetate/hexane) provided the propargyl amine as a white solid (5.2 g,86%).

Part C: To a solution of the propargyl amine of part B (8 g, 22.63 mmol)and powdered K₂CO₃ (8.8 g, 56.6 mmol) in N,N-dimethylformamide (150 mL)was added 3,4-dimethoxyphenol (6.98 g, 45 mmol) at ambient temperature.The composition was heated to 90 degrees Celsius for 36 hours. Thesolution was concentrated under high vacuum and the residue wasdissolved in ethyl acetate. The organic layer was washed with 1N NaOH,H₂O and dried over MgSO₄. Chromatography (on silica, ethylacetate/hexane) provided phenoxy propargyl amine as light yellow gel (10g, 90.9%).

Part D: A solution of NaOH (8.2 g, 200 mmol) in H₂O (30 mL) fromaddition funnel was added to a solution of the phenoxy propargyl amineof part C (10 g, 20.5 mmol) in ethanol (15 mL) and tetrahydrofuran (15mL) at ambient temperature. The resulting solution was then heated to 60degrees Celsius for 48 hours and at ambient temperature for 48 hours.The solution was concentrated in vacuo and diluted with water. Theaqueous layer was extracted with ether and acidified to pH=2. Vacuumfiltration of the white precipitate provided the acid as a white solid(9.4 g, quantitative yield).

Part E: To a solution of the acid of part D (9.4 g, 20.5 mmol), N-methylmorpholine (6.8 mL, 62 mmol), 1-hydroxybenzotriazole (8.3 g, 60 mmol)and O-tetrahydro-2H-pyran-yl-hydroxylamine (4.8 g, 40 mmol) inN,N-dimethylformamide (50 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.7 g,60 mmol). The resulting solution was then stirred at ambient temperaturefor 20 hours. The solution was concentrated under high vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith saturated NaHCO₃, H₂O and dried over Mg₂SO₄. Concentration in vacuoand chromatography (on silica, ethyl acetate/hexane) provided the THPamide as white foam (10 g, 89.7%).

Part F: To a solution of 4N HCl in dioxane (38 mL, 152 mmol)) was addeda solution of the amide of part E (8.5 g, 15.2 mmol) in methanol (8 mL)and dioxane (24 mL).The resulting composition was stirred at ambienttemperature for 80 minutes. Concentration in vacuo and titration withether provided hydroxamate HCl salt as a white solid (7.7 g,quantitative yield). HSMS calculated for C₂₃H₂₆N₂O₇S: 475.1461, found475.1539.

EXAMPLE 39 Preparation of4-[[4-(3,5-dimethoxyphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the propargyl amine of Part B, Example 38 (2 g,5.6 mmol) and powdered K₂CO₃ (1.9 g, 13.7 mmol) in N,N-dimethylformamide(20 mL) was added 3,5-dimethoxyphenol (2.18 g, 13.7 mmol) at ambienttemperature. The resulting composition was heated to 90 degrees Celsiusfor 36 hours. The solution was concentrated under high vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith 1N NaOH, H₂O and dried over MgSO₄. Chromatography (on silica, ethylacetate/hexane) provided phenoxy propargyl amine as light yellow gel(2.76 g, quantitative yield).

Part B: To a solution of the phenoxy propargyl amine of part A (2.75 g,5.6 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added NaOH(2.3 g, 56 mmol) in H₂O (10 mL) at ambient temperature. The solution wasthen heated to 60 degrees Celsius for 18 hours. The solution wasconcentrated in vacuo and diluted with water. The aqueous layer wasextracted with ether and acidified to pH=2. Vacuum filtration of whiteprecipitate provided the acid as white solid (2 g, 77.2%).

Part C: To a solution of the acid of part B (2 g, 4.3 mmol), alsocontaining N-methyl morpholine (1.9 mL, 17.2 mmol),1-hydroxybenzotriazole (1.74 g, 13.2 mmol) andO-tetrahydro-2H-pyran-yl-hydroxylamine (1.02 g, 8.6 mmol) inN,N-dimethylformamide (20 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.47 g,12.9 mmol). The resulting composition was stirred at ambient temperaturefor 20 hours. The solution was concentrated under high vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith saturated NaHCO₃, H₂O and dried over Mg₂SO₄. Concentration in vacuoand chromatography (on silica, ethyl acetate/hexane) provided the THPamide as white foam (2.4 g, quantitative yield).

Part D: To a solution of 4N HCl in dioxane (13 mL, 52 mmol)) was added asolution of the THP amide of part C (2.43 g, 4.35 mmol) in methanol (2mL) and dioxane (6 mL), and the composition was stirred at ambienttemperature for 80 minutes. Vacuum filtration of the precipitate andwashing with ether provided the hydroxamate HCl salt as a white solid(1.25 g, 56.3%). Analytical calculation for C₂₃H₂₆N₂O₇S.1.5HCl: C,52.20; H, 5.24; N, 5.29. Found: C, 52.00; H, 5.05; N, 5.17.

EXAMPLE 40 Preparation of4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the N-BOC carboxylic acid compound of part B.Example 37 (1.25 g, 2.47 mmol), N-methylmorpholine (1.00 g, 9.89 mmol)and 1-hydroxybenzotriazole hydrate (0.40 g, 2.96 mmol) inN,N-dimethylformamide (S mL) at ambient temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.616 g,3.21 mmol). After 5 minutes a solution ofO-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.39 g, 3.33 mmol) inN,N-dimethylformamide (2 mL) was added. After 2 days the pale yellowsolution was concentrated in vacuo to afford a residue which wasdissolved in ethyl acetate and washed successively with water (3×) andbrine and dried over sodium sulfate. Concentration afforded a residuethat was chromatographed on silica gel eluting with ethyl acetate/hexane(20/80) to afford the THP-protected hydroxamate as an oil (1.54 g,100%).

Part B: To a solution of THP-protected hydroxamate of part A (1.49 g,2.46 mmol) in dioxane (9 mL) and methanol (3 mL) was added 4 N HCl indioxane (10 mL, 40 mmol). After 1.5 hours at ambient temperature thesuspension was treated with diethyl ether (15 mL) and filtered to affordthe title hydroxamate (1.00 g, 89%) as a colorless powder. MS (CI) MH⁺calculated for C₁₉H₂₀N₂SO₇: 421, found 421. Analytical calculation forC₁₉H₂₀N₂SO₇.HCl: C, 49.95; H, 4.63; N, 6.13; Cl, 7.76; S, 7.02. Found:C, 49.82; H, 4.60; N, 5.98; Cl, 17.38; S, 7.10.

EXAMPLE 41 Preparation ofN-hydroxy-4-[[4-(3-methylphenoxy)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of propargylamine of part F, Example 9 (8.0 gm,22.6 mmol) and K₂CO₃ in N,N-dimethylformamide (30 mL) was added m-cresol(3.5 g, 33.9 mmol) and the solution was stirred at 90 degrees Celsiusfor 18 hours. The solution was diluted with H₂O and extracted with ethylacetate. The combined organic layers were washed with saturated NaCl anddried over MgSO₄. Chromatography (on silica, eluting with 10% ethylacetate/hexane) provided the 3-methyl phenoxyphenyl compound as a solid(10.3 g, 98%). Cal'd MS for C₂₄H₂₈SO₅ 441.1688, found 442.1697.

Part B: To a solution of 3-methyl phenoxyphenyl compound of part A (10.3g, 22.0 mmol) in tetrahydrofuran (50 mL) and ethanol (50 mL) was addedNaOH (8.9 g, 22.3 mol) and the solution was heated at 65 degrees Celsiusfor 24 hours. The solution was concentrated in vacuo and the aqueousresidue was acidified to pH=3. Vacuum filtration of the resultingprecipitate provided the acid as a white solid (9.0 g, 91%). MS cal'dfor C₂₂H₂₄NSO₅=414.1375. Found=414.1389.

Part C: To a solution of the acid of part B (9.0 g, 19.5 mmol) was added1-hydroxybenzotriazole (3.24 g, 23.9 mmol), N-methylmorpholine (6.58 mL,59.9 mmol), O-tetrahydro-2H-pyran-yl-hydroxylamine (3.5 g, 29.9 mmol)followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodimmide hydrochloride(5.35 g, 27.9 mmol). The solution was stirred at ambient temperature for18 hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄. Chromatography (on silica, eluting with 40% ethylacetate/hexane) provided the desired THP-protected hydroxamate as asolid (6.9 g, 67%). Analytical calculation for C₂₇H₃₃N₂SO₆:0.1H₂O: C,62.92, H, 6.49, N, 5.43, S, 6.23. Found: C, 62.69, H, 6.47, N, 5.57, S,6.33. Cal'd MS for C₂₇H₃₃N₂SO₆: 513.2059. Found 513.2071.

Part D: To a solution of THP-protected hydroxamate of part C (6.4 gm,12.5 mmol) in dioxane (56 mL) and methanol (19 mL) was added 4 NHCl/dioxane (40 mL). After stirring at ambient temperature for 1 hours,the solution was concentrated in vacuo. Trituration with ethyl etherprovided the title compound as a white solid (5.66 g, 97.4%). Cal'd MSfor C₂₂H₂₄N₂SO₅+1: 429.1484. Found M+1: 429.1493

EXAMPLE 42 Preparation of4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-N-hydroxy-1-(methylsulfonyl)-4-piperidinecarboxamide

Part A: To a solution of sulfone of part D, Example 32 (25 g, 67.3 mmol)in N,N-dimethylformamide was added potassium carbonate (23.3 g, 0.169mol) and sesamol (23.2 g, 0.164 mol). The solution was submerged in anoil bath at 90° C. and stirred for 25 hours. Ethyl acetate was added tothe solution, and the organic phase was washed with water, 1N NaOH andwater, dried over magnesium sulfate, filtered and concentrated in vacuo.Chromatography on silica, eluting with ethyl acetate/hexane (15/85)provided the ethyl ester compound as an oil (29.3 g, 82%).

Part B: To a solution of ethyl ester from part A (29.3 gm, 54.93 mmol)in ethanol (60 mL) and tetrahydrofuran (60 mL) was added a solution ofNaOH (21.9 g, 0.549 mol) in water 120 mL) and the solution was heated at65 degrees Celsius for 10 hours. The solution was concentrated in vacuoand the aqueous residue was acidified to pH=3. The solution wasextracted with ethyl acetate. The solution was dried over magnesiumsulfate, filtered and concentrated in vacuo to give the acid as a yellowfoam (25.6 g 92.1%).

Part C: To a solution of the acid of Part B (20.3 g, 40.15 mmol) inethyl acetate at zero degrees C. was bubbled gas HCl for 20 minutes. Thesolution stirred at Zero degrees Celsius for 1.5 hours. The precipitateformed was filtered and washed with ether to give the aminehydrochloride as a white solid (16.0 g, 93.5%)

Part D: To a solution of amine hydrochloride of part C (7.5 g, 17.0mmol) in methylene chloride (200 mL) was added methanesulfonyl chloride(2.0 g, 25.0 mol) and the solution was stirred at ambient temperaturefor 18 hours. The solution was washed with water and saturated NaCl,dried over magnesium sulfate, concentrated in vacuo to provide the acidas a white solid (6.97 g, 85%).

Part E: To a solution of the acid of part D (7.37 g, 15.0 mmol) wasadded 1-hydroxybenzotriazole (2.43 g, 18.0 mmol), N-methylmorpholine(4.94 mL, 45.0 mmol), O-tetrahydro-2H-pyran-yl-hydroxylamine (2.65 g,22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodimmidehydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambienttemperature for 18 hours. The solution was diluted with H₂O (400 mL) andextracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over MgSO₄. Chromatography (on silica, elutingwith 50% ethyl acetate/hexane) provided the desired THP-protectedhydroxamate as a solid (7.54 g, 85%).

Part F: To a solution of THP-protected hydroxamate of part E (6.32 gm,10.8 mmol) in dioxane (75 mL) and methanol (25 mL) was added 4 NHCl/dioxane (30 mL). After stirring at ambient temperature for 1 hour,the solution was concentrated in vacuo. Trituration with ethyl etherprovided the title compound. Chromatography (on silica, 5%methanol/ethyl acetate) provided the hydroxamate as a white solid (4.32g, 80%) Cal'd MS for C₂₂H₂₂N₂S₂O₉+1: 499.0845. Found 499.0848.

EXAMPLE 43 Preparation of4-[[4-(3,4-Dimethylphenoxyl)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: A mixture of the fluoro compound from part F, Example 9 (2.0 g,5.66 mmol), 3,4-dimethylphenol (2.0 g, 16.5 mmol), and potassiumcarbonate (2.3 g, 16.5 mmol) in N,N-dimethylformamide (15 mL) was heatedat 90 degrees Celsius overnight (about 18 hours) under an atmosphere ofnitrogen. The brown mixture was concentrated in vacuo and purified bychromatography (on silica, ethyl acetate/hexane) to afford the3,4-dimethylphenoxy phenyl compound as a clear, yellow oil (2.0 g, 79%yield). Analytical calculation for C₂₅H₂₉NO₅S: C, 65.91; H, 6.42; N,3.04; S, 7.04. Found: C, 65.76; H, 6.37; N, 3.03; S, 7.00.

Part B: A solution of the 3,4-dimethylphenoxy phenyl compound of part A(2.0, 4.93 mmol) and potassium hydroxide (1.7 g, 29.7 mmol) in a mixtureof ethanol (25 mL) and water (4 mL) was stirred at reflux for four hoursunder a nitrogen atmosphere. The solution was cooled with an ice bath,subsequently acidified with concentrated hydrochloric acid, andconcentrated to a crude residue. The crude residue,O-tetrahydo-2H-pyran-2-yl-hydroxylamine (0.88 g, 7.50 mmol),triethylamine (0.81 mL, 5.81 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride inacetonitrile (24 mL) was stirred at ambient temperature overnight. Themixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water, a saturated sodium bicarbonatesolution, water, and a saturated salt solution. After drying overmagnesium sulfate, the filtrate, as the THP-protected hydroxamate, wasconcentrated to a yellow foam.

Part C: The THP-protected hydroxamate (920 mg, 1.75 mmol) of part B wasdissolved in methanol (16 mL). Acetyl chloride (0.37 mL, 5.3 mmol) wasadded. After three hours, concentration followed by reverse phase HPLCafforded the title compound as a white solid (611 mg, 79%). MS (EI) MH⁺calculated for C₂₃H₂₆N₂O₅S: 443, found 443.

EXAMPLE 44 Preparation of4-[[4-(4-chlorophenyl)thiolphenyl]sulfonyl]-1-(propynyl)-4-piperidinecarboxylicacid, monohydrochloride and4-[[4-(4-chlorophenyl)thiolphenyl]sulfonyl]-N-hydroxy-1-(propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: A mixture of the fluoro compound from part F, Example 9 (2.0 g,5.66 mmol), 4-chlorothiophenol (1.0 g, 6.94 mmol), and potassiumcarbonate (1.1 g, 8.00 mmol) in N,N-dimethylformamide (12 mL) wasstirred overnight (about 18 hours) under an atmosphere of nitrogen atambient temperature. The mixture was concentrated in vacuo. The residuewas diluted with water and extracted with ethyl acetate. The organiclayer was washed with water and a saturated salt solution, dried overmagnesium sulfate, and concentrated in vacuo to a yellow oil. The oilwas purified by chromatography (on silica, ethyl acetate/hexane) toafford the 4-chlorophenylthiolphenyl compound as a white solid (2.0 g,75% yield). Analytical calculation for C₂₃H₂₄NO₄S₂C₁: C, 57.791; H,5.06; N, 2.93; S, 13.42; Cl, 7.42. Found: C, 57.57; H, 5.11; N, 2.94; S,13.19; Cl, 7.73.

Part B: The chorophenylthiophenyl compound from part A (2.04 g, 4.27mmol) was diluted with ethanol (30 mL) and water (5 mL). Potassiumhydroxide (1.55 g, 27.7 mmol) was added, and the mixture was heated atreflux for 3 hours. After complete reaction, the solution was cooled andwas acidified to pH=1-3 with concentrated HCl. The solvent was removedby rotary evaporation and the residue was azeotroped to dryness byrepeated addition of acetonitrile. The acid hydrochloride was furtherdried on a vacuum line, then carried as is through the couplingreaction. The saponification was presumed to be quantitative.

Part C: The carboxylic acid hydrochloride from the previous step (4.27mmol) was suspended in acetonitrile (20 mL). N-Methylmorpholine (about1.0 mL) was added, followed by O-tetrahydro-2H-pyran-2-yl-hydroxylamine(585 mg, 5 mmol). After 5 minutes,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 955mg, 5 mmol) was added. The mixture was stirred overnight (about 18hours), then solvent was removed by rotary evaporation, the residue wasdiluted with half-saturated NaHCO₃ solution (50 mL), and the product wasextracted into ethyl acetate (2×100 mL). In this example, an intractableemulsion complicated compound recovery. The combined organic layers weredried over MgSO₄, filtered through silica, concentrated, and subjectedto chromatography (flash silica, ethyl acetate/hexane) affording, onconcentration, the title O-THP-protected hydroxamate (162 mg, 7%, fromester) as a foam. MS (EI) MH⁺ calculated for C₂₁H₂₂N₂O₄S₂Cl: 450, found450. Because mass recovery was poor, the silica filter cake wasextracted with 1:1 methanol:ethyl actetate affording4-[[4-(4-chlorophenyl)thiolphenyl]sulfonyl]-1-(propynyl)-4-piperidinecarboxylicacid, monohydrochloride (540 mg, 26%)

Part D: The O-THP-protected hydroxamate of part C (441 mg, 0.80 mmol)was dissolved in methanol (2 mL). Acetyl chloride (0.2 mL, 3 mmol) wasadded. After three hours, concentration followed by reverse phase HPLCafforded the title hydroxamate compound as a pink solid (162 mg, 44%).MS (EI) MH⁺ calculated for C₂₁H₂₂N₂O₄S₂: 465, found 465.

EXAMPLE 45 Preparation of4-[[4-(Cyclopentylthio)phenyl)sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: The propargyl amine of part F, Example 9 (3.05 g, 8.5 mmol) wascombined with K₂CO₃ (1.38 g, 10 mmol), N,N-dimethylformamide (6 mL) andcyclopentyl mercaptan (1.02 mL, 10 mmol). The mixture was heated to 80degrees Celsius for 4 hours and 95 degrees Celsius for 2.5 hours,monitoring by TLC. Aqueous workup was accomplished using water (10 mL)and ethyl acetate (2×100 mL). The combined organic layers were driedover magnesium sulfate, concentrated, and chromatographed (flash silica;ethyl acetate/hexane eluant) affording the cyclopentylmercaptyl compoundas an oil (3.2 g, 86%)

Part B: The cyclopentylmercaptyl compound from part A (3.12 g 7.13 mmol)was diluted with ethanol (50 mL) and water (8 mL). Potassium hydroxide(2.59 g, 46.3 mmol) was added, and the mixture was heated at reflux for3.5 hours. After complete reaction, the solution was cooled and wasacidified to pH=1-3 with concentrated HCl. The solvent was removed byrotary evaporation and the residue was azeotroped to dryness by repeatedaddition of acetonitrile. The carboxylic acid hydrochloride was furtherdried on a vacuum line, then carried as is through the couplingreaction. The saponification was presumed to be quantitative.

Part C: The carboxylic acid hydrochloride from Part B (7.13 mmol) wassuspended in acetonitrile (50 mL). N-Methylmorpholine (ca. 2.0 mL) wasadded, followed by O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.05 g, 9mmol). After 5 minutes, EDC (1.72 g, 9 mmol) was added. The mixture wasstirred overnight (about 18 hours), then solvent was removed by rotaryevaporation. The residue was diluted with half-saturated NaHCO₃ solution(50 mL), and the product was extracted into ethyl acetate (2×100 mL).The combined organic layers were dried over MgSO₄, filtered throughsilica, concentrated, and subjected to chromatography (flash siilca,ethyl acetate/hexane) affording, on concentration, the O-THP-protectedhydroxamate (2.0 g, 51%, from ester) as a foam.

Part D: The O-THP-protected hydroxamate from Part D (2.00 g, 3.95 mmol)was dissolved in methanol (16 mL). Acetyl chloride (0.86 mL, 12 mmol)was added over 2 minutes. The reaction was stirred at ambienttemperature for 4 hours, then concentrated, with repeated addition ofchloroform and acetonitrile to effect drying. The title compoundprecipitated as a white solid (1.77 g, 98%). MS (EI) MH⁺ calculated forC₂₀H₂₆N₂O₄S₂: 422, found 422.

EXAMPLE 47 Preparation ofN-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,1-oxide andN-hydroxy-4-[[4-(phenylsulfinyl)-phenyl]sulfonyl-1-(2-propynyl)-4-piperidinecarboxamide

m-Chloroperbenzoic acid (57-86%, 120 mg) was added to a solution ofN-hydroxy-4-[[4-(phenylthio)phenyl]-sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide(title compound, Example 9) (215 mg, 0.5 mmol) in methanol (5 mL) atzero degrees Celsius. The reaction was permitted to warm slowly toambient temperature and after 16 hours, the mixture was passed through amicron filter and concentrated. Reverse phase HPLC (Delta Pak 50×300 mm;15 micron C₁₈ 100 Angstrom; 30 minute gradient method starting withdilute HCl (0.5 mL/4 L): acetonitrile 80:20, ending with 50:50)separated 5 major components. The first and second peaks off the columnafforded, upon concentration, 14 (6%) and 16 mg (7%) of two compounds,which were assigned as diastereomers ofN-Hydroxy-4-[[4-(phenylsulfinyl)-phenyl]sulfonyl-1-(2-propynyl)-4-piperidinecarboxamideon the basis of their NMR spectra. The third peak was unidentified. The4th peak was assigned by NMR asN-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,1-oxide (147 mg, 66%) MS (EI) MH⁺ calculated for C₂₁H₂₂N₂O₅S₂: 447,found 447. The last peak contained 73 mg of recovered 3-chlorobenzoicacid.

EXAMPLE 48 Preparation ofN-hydroxy-2,2-dimethyl-5-[(4-phenoxyphenyl)sulfonyl]-1,3-dioxane-4-carboxamide

Part A: A fresh sodium methoxide solution was prepared by slowly addinghexane-washed sodium spheres (9.4 g, 410 mmol) to methanol (1.0 L) atzero degrees Celsius. To this cooled solution was added the4-fluorothiophenol (50.0 g, 390 mmol) followed by methyl 2-chloroacetate (42.3 g, 390 mmol). After warming to ambient temperature thereaction was stirred overnight (about 18 hours). The methanol wasremoved in vacuo and the residue was taken up in ethyl acetate (300 mL).The organic layer was washed with water (2×-200 mL) and dried overMgSO₄. Concentrating afforded the methyl ester sulfide product as aclear oil (71.8 g, 92%).

Part B: To a solution of the methyl ester sulfide product of part A(71.8 g, 358 mmol) in 70% methanol/H₂O (1.0 L) was slowly added Oxone®(660 g, 1.08 mol). The mixture stirred overnight (about 18 hours) atambient temperature. The excess Oxone® was filtered off and the methanolwas removed from the filtrate in vacuo. The remaining aqueous solutionwas extracted with ethyl acetate (3×300 mL). The organic layers werewashed with water (2×-300 mL) and dried over MgSO₄. Concentratingafforded the sulfone product as a tan oil (82 g, 98%).

Part C: To a prepared slurry of potassium bicarbonate (1.0 g, 9.8 mmol)in 37% formaldehyde solution was added the sulfone product of part B(28.6 g, 123 mmol). The reaction was stirred for one hour and then asaturated solution of sodium sulfate (20 mL) was added. After stirringfor thirty minutes, the mixture was extracted with diethyl ether (4×-100mL). The organic layers were dried over MgSO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the sulfone diol product as aclear oil (15.3 g, 42%).

Part D: The sulfone diol product of Part C (1.3 g, 4.5 mmol) wasdissolved in acetone (40 mL) along with 2,2-dimethoxypropane (1.1 mL,9.0 mmol) and p-toluenesulfonic acid monohydrate (0.03 mg, 0.14 mmol)and the resulting composition was refluxed for 6 hours. After cooling,the mixture was neutralized with solid Na₂CO₃ (pH˜7), filtered, andconcentrated. The residue was dissolved in chloroform (50 mL) and washedwith water (2×-30 mL). Drying over MgSO₄, and concentrating gave thedimethyl ketal product as an opaque oil (1.4 g, 94%).

Part E: Phenol (0.6 g, 6.3 mmol) and cesium carbonate (2.0 g, 6.3 mmol)were added to a solution of the dimethyl ketal product (1.4 g, 4.2 mmol)of part D in N,N-dimethylformamide (20 mL). The mixture was heated at 90degrees Celsius for five hours, diluted with water (20 mL), andextracted with ethyl acetate (4×-100 mL). The organic layers were washedwith brine (1×-100 mL) and water (1×-100 mL). Concentrating afforded thephenol-O-phenol dimethyl ketal as a dark brown oil (1.51 g, 88%).

Part F: To a solution of the phenol-O-phenol dimethyl ketal product (1.5g, 3.4 mmol) of part E in tetrahydrofuran (10 mL) was added an aqueouslithium hydroxide solution (0.34 g, 14.8 mmol, in 5 mL of H₂O). Thereaction was stirred for two hours and then was diluted with water (15mL) and acidified via 30% HCl_(aq) to pH=3. The acidic solution wasextracted with diethyl ether (3×-100 mL). Drying over MgSO₄ andconcentrating afforded the carboxylic acid product as a brown oil (1.5g, quantitative yield).

Part G: To a solution of the carboxylic acid product of Part F (1.3 g,3.3 mmol) and N-hydroxybenzotriazole hydrate (0.54 g, 4.0 mmol) in DMF(15 mL) was added 4-methylmorpholine (1.67 g, 16.5 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.2 g, 10.2 mmol), and EDC(0.88 g, 4.6 mmol), respectively. After stirring overnight, the DMF wasremoved in vacuo and the residue was taken up in ethyl acetate/water(1:1, 50 mL). The organic layer was washed with brine (1×-200 mL) andwater (1×-20 mL) and dried over MgSO₄. Chromatography (on silica, ethylacetate/hexane) provided the THP-protected hydroxylamine product as awhite solid (0.36 g, 22%) as well as the decarboxylated by-product (0.27g, 24%).

Part H: To a solution of the THP-protected hydroxylamine product of PartG (0.36 g, 0.73 mmol) in dioxane (3 mL) and methanol (1 mL) was added 4N HCl in dioxane (2 mL). The reaction was stirred for five minutes andthen the solvents were removed in vacuo. Chromatography (reverse phaseC-18, acetonitrile/water) gave the title compound as a white solid (0.13g, 44%). MS (FAB) M⁺H calculated for C₁₉H₂₂NO₇S: 408, found 408.

EXAMPLE 49 Preparation oftetrahydro-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

Part A: To a solution of methyl 2-chloroacetate (322 g, 2.96 mol) inN,N-dimethylacetamide (1.0 L) were added thiophenol (400 g, 3.12 mol)and potassium carbonate (408 g, 2.96 mol). The reaction was stirred atambient temperature overnight(about 18 hours). After diluting with aminimal amount of water (800 mL), the mixture was extracted with ethylacetate (4×-1 L). The organic layers were washed with water (1×-800 mL),dried over MgSO₄, and concentrated to afford the sulfide product as aclear oil (614 g, quantitative yield).

Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) inmethanol (1000 mL) was added water (100 mL) and Oxone® (720 g, 1.17 mol)at twenty degrees Celsius. An exotherm to 67 degrees Celsius was noted.After two hours, the reaction was filtered and the cake washed well withmethanol. The filtrate was concentrated in vacuo. The residue was takenup in ethyl acetate and washed with brine, dried over MgSO₄, filtered,and concentrated in vacuo to give the sulfone as a crystalline solid(82.74 g, 94%).

Part C: To a solution of the sulfone of part B (60.0 g, 258 mmol) in DMA(350 mL) was added the dibromoethylthioether (76.9 g, 310 mmol),followed by potassium carbonate (78.3 g, 568 mmol). The mixture wasstirred five minutes before adding catalytic amounts of4-dimethylaminopyridine and tetrabutylammonium bromide. The reaction wasstirred overnight (about 18 hours), after which it was poured into astirring solution of 10% HCl_(aq) (2.5 L). The resulting precipitate wasfiltered and washed with hexane to remove the excess thioether. Dryingin vacuo overnight (about 18 hours) yielded the methylester thiopyran-Ph-p-F as a yellow powder (76.1 g, 93%).

Step D: To a solution of the methylester thiopyran -Ph-p-F of part C(4.0 g, 12.6 mmol) in N,N-dimethylacetamide (25 mL) were added cesiumcarbonate (6.1 g, 18.9 mmol) and thiophenol (2.1 g, 18.9 mmol). Themixture was stirred 2 hours at 90 degrees Celsius. The mixture wasdiluted with water (30 mL) and extracted with ethyl acetate (3×-100 mL).The organic layers were washed with brine (1×-75 mL) and water (1×-75mL) and was then dried over MgSO₄. Chromatography (on silica, ethylacetate/hexane) provided the phenyl-S-phenyl methyl ester as a yellowishsolid (3.6 g, 71%).

Step E: Potassium trimethylsilonate (1.24 g, 9.7 mmol) was added to asolution of the phenyl-S-phenyl methyl ester of part D (3.6 g, 8.8 mmol)in tetrahydrofuran (15 mL). The mixture was stirred 2-3 hours at ambienttemperature or until a solid precipitate developed. After the hydrolysiswas complete, N-methylmorpholine (2.9 mL, 26.4 mmol) was added followedby PyBrop (4.9 g, 10.6 mmol). The solution was stirred for lo minutes.Aqueous hydroxylamine (0.32 g, 9.7 mmol) was added and the mixturestirred for an additional 2 hours. After completion, the solvent wasremoved in vacuo. Chromatography (reverse phase C-18,acetonitrile/water) of the residue provided the title compound as an offwhite solid (0.82 g, 23%). MS (FAB) M⁺H calculated for C₁₈H₁₉NO₄S₃: 410,found 410.

EXAMPLE 50 Preparation of4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-thiopyran-4-carboxamide

Part A: Thiophenol (400 g, 3.12 mol) and potassium carbonate (408 g,2.96 mol) were added to a solution of methyl 2-chloroacetate (322 g,2.96 mol) in N,N-dimethylacetamide (1.0 L). The reaction was stirred atambient temperature overnight (about 18 hours). After diluting with aminimal amount of water (800 mL), the mixture was extracted with ethylacetate (4×-1 L). The organic layers were washed with water (1×-800 mL),dried over MgSO₄, and concentrated to afford the sulfide product as aclear oil (614 g, quantitative yield).

Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) inmethanol (1000 mL) was added water (100 mL) and Oxone® (720 g, 1.17 mol)at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted.After two hours, the reaction was filtered and the cake was washed wellwith methanol. The filtrate was concentrated in vacuo. The residue wastaken up in ethyl acetate and washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo to give the methyl ester sulfone asa crystalline solid (82.74 g, 94%).

Part C: To a solution of the methyl ester sulfone product of part B(60.0 g, 258 mmol) in N,N-dimethylacetamide (350 mL) was added2,2-dibromoethylthioether (76.9 g, 310 mmol) followed by potassiumcarbonate (78.3 g, 568 mmol). The mixture was stirred five minutesbefore adding catalytic amounts of 4-dimethylaminopyridine andtetrabutylammonium bromide. The reaction was stirred overnight (about 18hours), after which it was poured into a stirring solution of 10%HCl_(aq) (2.5 L). The resulting precipitate was filtered and washed withhexane to remove the excess thioether. Drying in vacuo overnight (about18 hours) yielded the thiopyran methyl ester as a yellow powder (76.1 g,93%).

Step D: To a solution of the thiopyran methyl ester of part C (30.0 g,94 mmol) in tetrahydrofuran (250 mL) was added potassiumtrimethylsilonate (28.9 g, 226 mmol). The mixture was stirred 2-3 hoursat ambient temperature or until a solid precipitate developed. After thehydrolysis was complete, the solvent was removed in vacuo. Water (200mL) was added and the mixture was washed with diethyl ether (1×-200 mL).The aqueous layer was cooled to zero degrees Celsius and 10% HCl_(aq)was slowly added until a precipitate formed. The solid was collected anddried in vacuo with phosphorous pentoxide to afford the thiopyrancarboxylic acid as a yellow solid (17.8 g, 62%).

Part E: To a solution of the thiopyran carboxylic acid of part D (17.8g, 58.5 mmol) in N,N-dimethylformamide (100 mL) was addedN-methylmorpholine (19.3 mL, 176 mmol) followed byN-hydroxybenzotriazole hydrate (9.5 g, 70.2 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (10.3 g, 87.8 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.8 g,87.8 mmol). The mixture was stirred three hours and was then dilutedwith water (100 mL). The mixture was extracted with ethyl acetate(4×-200 mL). Organic layers were washed with an aqueous saturatedpotassium carbonate solution (1×-200 mL), 1% HCl_(aq), and brine (1×-200mL). Drying over MgSO₄ and concentrating in vacuo afforded the titlecompound as an off white solid (30.8 g, quantitative yield). MS (FAB)M⁺H calculated for C₁₇H₂₂FNO₅S₂: 404, found 404.

EXAMPLE 51 Preparation ofTetrahydro-N-hydroxy-4-[[4-[(4-methoxypheny)thio]phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of Example 50 (6.0 g, 14.9mmol) in N,N-dimethylacetamide (25 mL) was added 4-methoxy thiophenol(2.5 g, 17.8 mL), followed by potassium carbonate (6.2 g, 44.7 mmol).The reaction was heated at 60 degrees Celsius for three hours. Thereaction mixture was diluted with water (25 mL) and extracted with ethylacetate (4×-100 mL). The organic layers were washed with water (2×-50mL) and dried over MgSO₄. Concentrating in vacuo provided theTHP-protected-Phenyl-S-pPhenyl-OMe product as a yellowish solid (9.2 g,quantitative yield).

Part B: To a solution of the THP-protected-Phenyl-S-pPhenyl-OMe productfrom part A (9.2 g, 14.9 mmol) in dioxane was slowly added 4N HCl indioxane (10 mL). After stirring overnight (about 18 hours), the solventwas removed. Chromatography on the resultant residue (reverse phaseC-18, acetonitrile/water) gave the title compound as a white solid (1.84g, 28.3%). MS (FAB) M⁺H calculated for C₁₉H₂₁NO₅S₃: 440, found 440.

EXAMPLE 52 Preparation ofTetrahydro-N-hydroxy-4-[(4-phenylthio)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide1,1-dioxide

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5mmol) in methylene chloride (100 mL) cooled to zero degrees Celsius wasslowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol). Themixture was stirred one hour at zero degrees Celsius followed by anadditional 3 hours as the temperature rose to ambient conditions. Water(200 mL) was added and the mixture was neutralized with 10% ammoniumhydroxide (100 mL). The organic layer was washed with water (1×-200 mL)and dried over MgSO₄. Concentrating in vacuo provided an orangish oil(3.5 g, 33%). The water/10% ammonium hydroxide solution was saturatedwith sodium chloride and extracted with ethyl acetate (2×-400 mL).Organic layer was dried over MgSO₄ and concentrated to afford theTHP-protected sulfone-thiopyran-p-F compound as an orange foam (6.1 g,57%).

Part B: To a solution of the THP-protected sulfone-thiopyran-p-F fromPart A (9.6 g, 22 mmol) in N,N-dimethylacetamide (120 mL) was addedthiophenol (2.9 g, 26.4 mL), followed by potassium carbonate (9.1 g, 66mmol). The reaction was heated at 60 degrees Celsius for four hours. Thereaction mixture was diluted with water (25 mL) and extracted with ethylacetate (4×-100 mL). The organic layers were washed with water (2×-50mL) and dried over MgSO₄. Chromatography (on silica, ethylacetate/hexane) provided the THP-protected-phenyl-S-phenyl product as anorange oil (5.1 g, 43%).

Part C: To a solution of the THP-protected-phenyl-S-phenyl product frompart B (5.1 g, 9.4 mmol) in dioxane was slowly added 4N HCl in dioxane(10 mL). After stirring overnight (about 18 hours), the solvent wasremoved. Chromatography of the resultant residue (reverse phase C-18,acetonitrile/water) gave the title compound as a pink solid (1.2 g,29%). MS (FAB) M⁺H calculated for C₁₈H₁₉NO₆S₃: 442, found 442.

EXAMPLE 53 Preparation ofTetrahydro-N-hydroxy-4-[[4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]-phenyl]-sulfonyl]-2H-thiopyran-4-carboxamide1,1-dioxide, monohydrochloride

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5mmol) in methylene chloride (100 mL) cooled to zero degrees Celsius wasslowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol). Themixture was stirred one hour at zero degrees Celsius followed by anadditional 3 hours as the temperature rose to ambient conditions. Water(200 mL) was added and the mixture was neutralized with 10% ammoniumhydroxide (100 mL). The organic layer was washed with water (1×-200 mL)and dried over MgSO₄. Concentrating in vacuo provided an orangish oil(3.5 g, 33%). The water/10% ammonium hydroxide solution was saturatedwith sodium chloride and extracted with ethyl acetate (2×-400 mL).Organic layer was dried over MgSO₄, and concentrated to afford theTHP-protected sulfone-thiopyran-p-F as an orange foam (6.1 g, 57%).

Part B: To a solution of the THP-protected sulfone-thiopyran-p-F from A(6.0 g, 13.8 mmol) in N,N-dimethylformamide (25 mL) was added4-(1H-1,2,4-triazol-1-yl)phenol (4.4 g, 27.5 mmol), followed by cesiumcarbonate (13.4 g, 41.4 mmol). The reaction was heated at 95 degreesCelsius for five hours. The reaction mixture was diluted with water (25mL) and extracted with ethyl acetate (4×-100 mL). The organic layerswere washed with water (2×-50 mL) and dried over MgSO₄. Concentratingafforded the THP-protected phenyl-O-phenyl triazole product as a tansolid (9.7 g, quantitative yield).

Part C: To a solution of the crude THP-protected phenyl-O-phenyltriazole product from B (8.0 g, 13.8 mmol) in acetonitrile (40 mL) wasslowly added 10% HCl_(aq) (100 mL). After stirring overnight (about 18hours), the acetonitrile was removed. The resultant precipitate wascollected, giving the title compound as a tan solid (1.3 g, 18%). MS(FAB) M⁺H calculated for C₂₀H₂₁ClN₄O₇S₂: 493, found 493.

EXAMPLE 54 Preparation of4-[[4-[4-(2-aminoethyl))phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-thiopyran-4-carboxamide1,1-dioxide monohydrochloride

Part A: To a solution of the title compound of Example 50 (13.0 g, 24.5mmol) in methylene chloride (100 mL) cooled to zero degrees Celsius wasslowly added 50-60% m-chloroperbenzoic acid (17.1 g, 49.5 mmol). Themixture was stirred one hour at zero degrees Celsius followed by anadditional 3 hours as the temperature rose to ambient conditions. Water(200 mL) was added and the mixture was neutralized with 10% ammoniumhydroxide (100 mL). The organic layer was washed with water (1×-200 mL)and dried over MgSO₄. Concentrating in vacuo provided an orangish oil(3.5 g, 33%). The water/10% ammonium hydroxide solution was saturatedwith sodium chloride and extracted with ethyl acetate (2×-400 mL). Theorganic layer was dried over MgSO₄ and concentrated to afford theTHP-protected sulfone-thiopyran-p-F as an orange foam (6.1 g, 57%).

Part B: To a solution of the THP-protected sulfone-thiopyran-p-F from A(6.0 g, 13.8 mmol) in N,N-dimethylacetamide (25 mL) was added tyramine(3.8 g, 28 mmol) followed by cesium carbonate (13.6 g, 42 mmol). Thereaction was heated at 95 degrees Celsius for five hours. Removing theN,N-dimethylacetamide in vacuo afforded a brown solid (20 g).Chromatography (reverse phase, C-18, acetonitrile/water) gave theTHP-protected tyramine product as a tan oil (1.0 g, 13%).

Part C: To a solution of the crude THP-protected tyramine product frompart B (1.0 g, 1.8 mmol) in acetonitrile (40 mL) was slowly added 10%HCl_(aq) (100 mL). After stirring overnight (about 18 hours), theacetonitrile was removed. The resultant precipitate was collected,giving the title compound as a tan solid (0.9 g, 99%). MS (FAB) M⁺Hcalculated for C₂₀H₂₅ClN₂O₇S₂: 469, found 469.

EXAMPLE 55 Preparation of4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide

Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol)was added to methanol (1000 mL) at two degrees Celsius. The reaction wasstirred at ambient temperature for forty five minutes at which time thesodium had dissolved. The solution was chilled to five degrees Celsiusand p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed bymethyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred atambient temperature for four hours, filtered, and concentrated in vacuoto give the sulfide as a clear colorless oil (75.85 g, 97%).

Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) inmethanol (1000 mL) were added water (100 mL) and Oxone® (720 g, 1.17mol) at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted.After two hours, the reaction was filtered and the cake was washed wellwith methanol. The filtrate was concentrated in vacuo. The residue wastaken up in ethyl acetate and washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo to give the sulfone as a crystallinesolid (82.74 g, 94%).

Part C: To a solution of the sulfone from part B (28.5 g, 0.123 mol) inN,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g,0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol),4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide(1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hours) atambient temperature. The reaction was slowly poured into 1N HCl (300mL), the resultant solid filtered and the cake washed well with hexanes.The solid was recrystallized from ethyl acetate/hexanes to give thepyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculatedfor C₁₃H₁₅O₅S₁F₁: 303, found 303.

Part D: In dry equipment under nitrogen, the pyran compound from part C(8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and asolution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in drytetrahydrofuran (15 mL) was added at ambient temperature. After ninetyminutes, water (100 mL) was added and the solution concentrated invacuo. The residue was taken up in water and extracted with ethylacetate to remove unreacted starting material. The aqueous solution wastreated with 6N HCl until pH=1. The slurry was extracted with ethylacetate and the combined extracts washed with water, dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was heated in diethylether, the solid filtered and dried to give the carboxylic acid as acrystalline solid (5.78 g, 76%). HRMS (ES−) M−H calculated forC₁₂H₁₃O₅S₁F₁: 287.04, found 287.04.

Part E: In dry equipment under nitrogen, the carboxylic acid from part D(9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL)and the remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol),N-methylmorpholine (10.4 mL, 94.8 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g,44.2 mmol). After three hours at ambient temperature, the reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith water, 5% KHSO₄, saturated NaHCO₃, brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Chromatography (on silica, ethylacetate/hexanes) provided the title compound as a crystalline solid (9.7g, 80%). HRMS (ES+) MH+ calculated for C₁₇H₂₂NO₆S₁F₁: 388.12, found388.12.

EXAMPLE 56 Preparation of4-[[4-(3,4-difluorophenoxy)-phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added 3,4-difluorophenol (1.0g, 7.7 mmol), followed by cesium carbonate (6.6 g, 20.2 mmol). Thereaction was heated at 95 degrees Celsius for five hours. Removing theN,N-dimethylacetamide in vacuo afforded a brown solid (8.3 g,quantitative). Chromatography (reverse phase, C-18, acetonitrile/water)gave the THP-protected difluoro product in solution.

Part B: To the collected THP-protected difluoro product from A inacetonitrile/water (50 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about 18 hours), the acetonitrile was removed. Theresultant precipitate was collected, giving the title compound as awhite solid (1.02 g, 48.6%). MS (FAB) M⁺H calculated for C₁₈H₁₇FNO₆S:414, found 414.

EXAMPLE 57 Preparation ofTetrahydro-N-hydroxy-4-[[4-(4-iodophenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added 4-iodophenol (1.7 g, 7.8mmol), followed by cesium carbonate (6.6 g, 20.2 mmol). The reaction washeated at 95 degrees Celsius for five hours. Removing theN,N-dimethylacetamide in vacuo afforded a brown solid (5.7 g,quantitative) Chromatography (reverse phase, C-18, acetonitrile/water)gave the THP-protected iodo product in solution.

Part B: To the solution of the crude THP-protected iodo product from Ain acetonitrile/water (40 mL) was slowly added 10% HCl_(aq) (100 mL).After stirring overnight (about 18 hours), the acetonitrile was removed.The resultant precipitate was collected, giving the title compound as awhite solid (2.6 g, 99%). MS (FAB) M⁺H calculated for C₁₈H₁₈INO₆S: 504,found 504.

EXAMPLE 58 Preparation ofTetrahydro-N-hydroxy-4-[[4-(2,4,5-trifluorophenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added 2,4,5-trifluorophenol(1.2 g, 7.8 mmol), followed by cesium carbonate (10.1 g, 31.0 mmol). Thereaction was heated at 95 degrees Celsius for thirty-two hours.Removinging the N,N-dimethylacetamide in vacuo afforded a brown solid(5.7 g, quantitative). Chromatography (reverse phase, C-18,acetonitrile/water) gave the THP-protected phenol product (1.2 g, 44%).

Part B: To the solution of the crude THP-protected phenol product fromPart A (1.2 g, 2.3 mmol) in acetonitrile/water (40 mL) was slowly added10% HCl_(aq) (100 mL). After stirring overnight (about 18 hours), theacetonitrile was removed. The resultant precipitate was collected,giving the title compound as a white solid (0.79 g, 79%). MS (FAB) M⁻Hcalculated for C₁₈H₁₆F₃NO₆S: 430, found 430.

EXAMPLE 59 Preparation of4-[[4-(3,5-dichlorophenoxy)-phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added 3,5-dichlorophenol (1.3g, 7.8 mmol), followed by cesium carbonate (6.6 g, 20.2 mmol). Thereaction was heated at 95 degrees Celsius for twelve hours. Removing theN,N-dimethylacetamide in vacuo afforded a brown solid (5.7 g,quantitative). The residue was taken up in acetonitrile/water (20 mL)and acidified to pH=6. A white precipitate formed and was collectedaffording the THP-protected product as a white cake (1.8 g, 64%).

Part B: To the THP-protected product from Part A (1.8 g, 3.4 mmol) inacetonitrile/water (20 mL) was slowly added 10% HCl_(aq) (40 mL). Afterstirring overnight (about 1 hours), the acetonitrile was removed. Theresultant precipitate was collected, giving the title compound as awhite solid (0.71 g, 47%) MS (FAB) M⁺H calculated for C₁₈H₁₇Cl₂NO₆S:447, found 447.

EXAMPLE 59 Preparation ofTetrahydro-N-hydroxy-4-[[4-[[5-(trifluoromethyl)-2-pyridinyl]thio]phenyl]sulfonyl]-2H-pyran-4-carboxamidemonohydrochloride

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added5-(trifluoromethyl)-2-pyridinyl thiophenol (1.4 g, 7.8 mmol), followedby potassium carbonate (2.2 g, 15.6 mmol). The reaction was heated at 65degrees Celsius for twelve hours. Removing the N,N-dimethylacetamide invacuo afforded a brown solid (5.4 g, quantitative). Chromatography(reverse phase, C-18, acetonitrile/water) gave the THP-protected productin solution.

Part B: To the solution of the crude THP-protected product from Part Ain acetonitrile/water (40 mL) was slowly added 10% HCl_(aq) (40 mL).After stirring overnight (about 18 hours), the acetonitrile was removed.The resultant precipitate was collected, giving the title compound as awhite solid (0.20 g, 8%). MS (FAB) M⁺H calculated for C₁₈H₁₇F₃N₂O₅S₂:463, found 463.

EXAMPLE 60 Preparation of4-[[4-(3,4-dichlorophenyl]-thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added 3,4-dichlorothiophenol(1.4 g, 7.8 mmol) followed by potassium carbonate (2.2 g, 15.6 mmol).The reaction was heated at 70 degrees Celsius for six hours. Removingthe N,N-dimethylacetamide in vacuo afforded a brown solid (5.6 g,quantitative). Chromatography (reverse phase, C-18, acetonitrile/water)gave the THP protected product in solution.

Part B: To the solution of the THP-protected product from Part A inacetonitrile/water (40 mL) was slowly added 10% HCl_(aq) (40 mL). Afterstirring overnight (about 18 hours), the acetonitrile was removed. Theresultant precipitate was collected, giving the title compound as awhite solid (1:5 g, 62%). MS (FAB) M⁺H calculated for C₁₈H₁₇Cl₂NO₅S:463, found 463.

EXAMPLE 61 Preparation of4-[[4-[[2-amino-4-(trifluoromethyl)phenyl]thio]phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a solution of the title compound of Example 55 (2.0 g, 5.2mmol) in N,N-dimethylacetamide (6 mL) was added2-amino-4-(trifluoromethyl)thiophenol hydrochloride (1.8 g, 7.8 mmol),followed by potassium carbonate (3.6 g, 26 mmol). The reaction washeated at 70 degrees Celsius for eight hours. Removing thedimethylacetamide in vacuo afforded a brown solid (14 g, quantitative).Chromatography (reverse phase, C-18, acetonitrile/water) gave the THPprotected product in solution.

Part B: To the solution of the THP-protected product inacetonitrile/water (40 mL) was slowly added 10% HCl_(aq) (40 mL). Afterstirring overnight (about 18 hours), the acetonitrile was removed. Theresultant precipitate was collected, giving the title compound as awhite solid (1.3 g, 52%). MS (FAB) M⁺H calculated for C₁₈H₁₇Cl₂NO₆S:477, found 477.

EXAMPLE 62 Preparation ofTetrahydro-4[[4-(4-phenyl-1-piperidinyl)phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol)was added to methanol (1000 mL) at two degrees Celsius. The reaction wasstirred at ambient temperature for forty-five minutes at which time thesodium had dissolved. The solution was chilled to five degrees Celsiusand p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed bymethyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred atambient temperature for four hours, filtered, and concentrated in vacuoto give the sulfide as a clear colorless oil (75.85 g, 97%).

Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) inmethanol (1000 mL) was added water (100 mL) and Oxone® (720 g, 1.17 mol)at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted.After two hours, the reaction was filtered and the cake was washed wellwith methanol. The filtrate was concentrated in vacuo. The residue wastaken up in ethyl acetate and washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo to give the sulfone as a crystallinesolid (82.74 g, 94%).

Part C: To a solution of the sulfone from part B (28.5 g, 0.123 mol) inN,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g,0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol),4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide(1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hours) atambient temperature. The reaction was slowly poured into 1N HCl (300mL), the resultant solid filtered and the cake washed well with hexanes.The solid was recrystallized from ethyl acetate/hexanes to give thepyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculatedfor C₁₃H₁₅O₅S₁F₁: 303, found 303.

Part D: To a solution of the pyran compound from part C (1.21 g, 4.0mmol) in dimethyl sulfoxide (10 mL) were added cesium carbonate (3.26 g,10 mmol) and 4-phenylpiperidine (0.64 g, 4.0 mmol) in methyl sulfoxide(10 mL). The slurry was stirred at 90 degrees Celsius for two hours. Thereaction was cooled, diluted with water and extracted with ethylacetate. The combined organic layers were washed with 5% KHSO₄,saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentratedin vacuo. The resultant solid was slurried in diethyl ether, filteredand dried to give the N-substituted piperidine as a white solid (1.2 g,67%). MS (FAB+) MH+ calculated for C₂₄H₂₉N₁O₅S₁, 444, found 444.

Part E: To a slurry of the N-substituted piperidine from part D (815 mg,1.84 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 50%sodium hydroxide (3 mL). After twenty-four hours at ambient temperature,the reaction was concentrated in vacuo. The slurry was diluted withwater (10 mL) and 6N HCl was added until the pH=7. Vacuum filtration ofthe resulting precipitate provided the acid as a white solid (705 mg,89%). MS (FAB+) MH+ calculated for C₂₃H₂₇N₁O₅S₁: 430, found 430.

Part F: In dry equipment under nitrogen, the carboxylic acid from part E(620 mg, 1.44 mmol) was slurried in methylene chloride (10 mL) andN,N-dimethylformamide (3 mL) and the remaining reagents were added tothe slurry in the following order: bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (810 mg, 1.73 mmol), N-methylmorpholine (0.5 mL,4.34 mmol), and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (190 mg, 1.59mmol). After four hours at ambient temperature, the reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith water, brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Chromatography (on silica, ethyl acetate/hexanes) provided theTHP-protected hydroxamate as a white solid (630 mg, 83%). MS (FAB+) MH+calculated for C₂₈H₂N₂O₆S₁: 529, found 529.

Part G: To a slurry of the THP-protected hydroxamate from part F (600mg, 1.14 mmol) in dioxane (1.5 mL) was added a 4N HCl dioxane solution(1.5 mL) and methanol (1.5 mL). After two hours at ambient temperaturethe reaction was poured into diethyl ether (100 mL). Vacuum filtrationof the resulting precipitate provided the title compound as a lightbeige solid (500 mg, 91%). MS (FAB+) M+Li calculated for C₂₃H₂₈N₂O₅S₁,445, found 445.

EXAMPLE 63 Preparation of4-[[4-[4-(1,3-Benzodioxol-5-yloxy)-1-piperidinyl]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,monohydrochloride

Part A: In dry equipment under nitrogen, 4-hydroxypiperidine (20.2 g,0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol)was added at such a rate that the temperature remained below 30 degreesCelsius. After stirring at ambient temperature for four hours, thereaction was concentrated in vacuo. The residue was taken up in ethylacetate, washed with water, 5% KHSO₄, saturated NaHCO₃, brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to give the BOCpiperidine as a white solid (37.7 g, 94%).

Part B: In dry equipment under nitrogen, the BOC piperidine from part A(5.0 g, 24.8 mmol) in dry tetrahydrofuran (100 mL) was cooled to zerodegrees Celsius and triphenylphosphine (9.77 g, 37.3 mmol) was added.After fifteen minutes of stirring at zero degrees Celsius, sesamol (5.15g, 37.3 mmol) was added to the reaction followed by the dropwiseaddition of diethylazodicarboxylate (5.87 mL, 37.7 mmol). The reactionwas stirred for thirty minutes at zero degrees Celsius and then atambient temperature for twenty hours. The reaction was concentrated invacuo. The residue was slurried in diethyl ether, the triphenylphosphine oxide filtered off and the filtrate concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted DOC piperidine as a white solid (3.14 g, 39%).

Part C: To a slurry of the substituted BOC piperidine from part B (3.14g, 9.8 mmol) in dioxane (15 ml) was added a 4N HCl dioxane solution (15mL). After three hours at ambient temperature, the reaction wasconcentrated in vacuo. The residue was slurried in diethyl ether andvacuum filtration of the resulting precipitate provided thehydrochloride salt as a white solid (2.3 g, 100%).

Part D: To a slurry of the hydrochloride salt from part C (0.93 g, 3.6mmol) in N,N-dimethylformamide (10 mL) were added cesium carbonate (2.93g, 9 mmol) and the title compound of Example 55 (1.16 g, 3.0 mmol). Theslurry was stirred at 90 degrees Celsius for twenty four hours. Thereaction was concentrated in vacuo. The residue was taken up in ethylacetate, washed with water, 5% KHSO₄, saturated NaHCO₃, brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (onsilica, ethyl acetate/hexanes) provided the substituted THP-protectedhydroxamate as a white solid (640 mg, 36%). MS (FAB+) MH+ calculated forC₂₉H₃₆N₂O₉S₁: 589, found 589.

Part E: To a slurry of the THP-protected hydroxamate from part D (600mg, 1.02 mmol) in dioxane (3 mL) were added a 4N HCl dioxane solution (3mL) and methanol (3 mL). After one hour at ambient temperature, thereaction was poured into diethyl ether (100 mL). Vacuum filtration ofthe resulting precipitate provided the title compound as a light beigesolid (440 mg, 80%). HRMS (ES+) MH+ calculated for C₂₄H₂₈N₂O₈S₁: 505.16,found 505.16.

EXAMPLE 64 Preparation ofTetrahydro-N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.48 g, 9mmol) in N,N-dimethylformamide (20 mL) were added cesium carbonate (8.8g, 27 mmol) and p-methoxyphenol (2.23 g, 18 mmol). The slurry wasstirred at 95 degrees Celsius for twenty four hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP-protected hydroxamate as a beige foam (3.82 g, 86%). MS(FAB+) MH+ calculated for C₂₄H₂₉N₁O₈S₁: 492, found 492.

Part B: To a slurry of the THP-protected hydroxamate from part A (3.6 g,7.33 mmol) in dioxane (18 mL) were added a 4N HCl dioxane solution (18mL) and methanol (18 mL). After fifteen minutes at ambient temperature,the reaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (2.1 g, 70%). HRMS (ES+) MH+ calculated for C₁₉H₂₁N₁O₇S₁: 408.11,found 408.11.

EXAMPLE 65 Preparation ofTetrahydro-N-hydroxy-4-[[4-(4-methoxyphenylthio)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8mmol) in N,N-dimethylformamide (20 mL) were added potassium carbonate(1.33 g, 9.6 mmol) and p-methoxybenzenethiol (1.48 mL, 12 mmol). Theslurry was stirred at 65 degrees Celsius for twenty-four hours. Thereaction was concentrated in vacuo. The residue was taken up in ethylacetate, washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the substituted THP-protected hydroxamate as a white foam (4.1g, 100%). HRMS (ES+) M+NH₄ ⁺ calculated for C₂₄H₂₉N₁O₇S₂: 525.17, found525.17.

Part B: To a slurry of the THP-protected hydroxamate from part A (4.0 g,7.9 mmol) in dioxane (20 mL) was added a 4N HCl dioxane solution (20 mL)and methanol (20 mL). After fifteen minutes at ambient temperature, thereaction was diluted with ethyl acetate, washed with water, dried overNa₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (2.21 g, 67%). HRMS (ES+) MH+ calculated for C₁₉H₂₁N₁O₆S₂: 424.09,found 424.09.

EXAMPLE 66 Preparation of4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a slurry of the title compound of Example 55 (530 mg, 1.38mmol) in dioxane (5 mL) was added a 4N HCl dioxane solution (5 mL) andmethanol (5 mL). After fifteen minutes at ambient temperature thereaction was concentrated in vacuo. Reverse phase chromatography (onsilica, acetonitrile/water) provided the title compound as a beige solid(140 mg, 34%): HRMS (ES+) M+NH₄ ⁺ calculated for C₁₂H₁₄N₁O₅S₁F₁: 321.09,found 321.09.

EXAMPLE 67 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-piperidinyloxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: In dry equipment under nitrogen,4-hydroxy-N-t-(butoxycarbonyl)piperidine (844 mg, 4.2 mmol) was added to60% sodium hydride (210 mg, 5.25 mmol) in dry N,N-dimethylformamide (10mL) at zero degrees Celsius. The slurry was stirred for two hours atambient temperature. At five degrees Celsius, the title compound ofExample 55 (1.35 g, 3.5 mmol) was added and the reaction heated to 50degrees Celsius for three hours. The reaction was cooled, quenched withwater, and concentrated in vacuo. The residue was taken up in ethylacetate, washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the substituted THP-protected hydroxamate as a white foam (283mg, 14%).

MS (FAB+) MH+ calculated for C₂₇H₄₀N₂O₉S₁: 569, found 569.

Part B: To a slurry of the THP-protected hydroxamate from part A (530mg, 0.93 mmol) in dioxane (5 mL) were added a 4N HCl dioxane solution (5mL) and methanol (5 mL). After fifteen minutes at ambient temperaturethe reaction was concentrated in vacuo. Reverse phase chromatography (onsilica, acetonitrile/water buffered with 0.01% HCl) provided the titlecompound as a beige solid (240 mg, 62%). HRMS (ES+) MH+ calculated forC₁₇H₂₄N₂O₆S₁: 385.14, found 385.14.

EXAMPLE 68 Preparation oftetrahydro-N-hydroxy-4-[[4-[(4-phenylmethyl)amino]phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: In a solid phase reaction vessel, benzylamine (11.0 mL, 100mmol) was added to Resin II (in a procedure described hereinafter; 5.0g, 4.55 mmol) swollen in dry 1-methyl-2-pyrrolidinone (40 mL). Thereaction was heated to 100 degrees Celsius for forty-eight hours withgood shaking. The resin was transferred to a frit and washed four timeswith N,N-dimethylformamide (30 mL), four times with methanol (30 mL),four times with methylene chloride (30 mL), and dried. The dried resinwas transferred to a flask and a solution of 95% trifluoroacetic acid/5%water (50 mL) was added. The slurry was stirred for one hour, filteredand the cake was washed with methylene chloride. The combined filtrateswere concentrated in vacuo. The residue was dissolved in ethyl acetateand saturated sodium bicarbonate solution was added until pH=7. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Reverse phase chromatography (on silica, acetonitrile/waterbuffered with 0.01% HCl) provided the title compound as a reddish solid(1.01 g, 52%). HRMS (ES+) M+NH₄ ⁺ calculated for C₁₉H₂₂N₂O₅S₁: 408.16,found 408.16.

EXAMPLE 69 Preparation ofTetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1 mL, 16 mmol). The slurrywas stirred at 95 degrees Celsius for nineteen hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS(ES+) MH+ calculated for C₂₄H₂₆N₁O₈S₁F₃: 546.14, found 546.14.

Part B: To a slurry of the THP-protected hydroxamate from part A (4.0 g,7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20mL) and methanol (20 mL). After fifteen minutes at ambient temperature,the reaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (2.2 g, 65%). HRMS (ES+) M+NH₄ ⁺ calculated for C₁₉H₁₈N₁O₇S₁F₃:479.11, found 479.11.

EXAMPLE 70 Preparation of4-[[4-(3,5-difluorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8g, 27 mmol) and 3,5-difluorophenol (2.1 g, 16 mmol). The slurry wasstirred at 95 degrees Celsius for forty-eight hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP-protected hydroxamate as a beige foam (3.23 g, 81%).HRMS (ES+) MH+ calculated for C₂₃H₂₅N₁O₇S₁F₂: 498.14, found 498.14.

Part B: To a slurry of the THP-protected hydroxamate from part A (3.2 g,6.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20mL) and methanol (20 mL). After fifteen minutes at ambient temperaturethe reaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue wasslurried in diethyl ether and vacuum filtration of the resultingprecipitate provided the title compound as a white solid (1.5 g, 57%).HRMS (ES+) M+NH₄ ⁺ calculated for C₁₈H₁₇N₁O₆S₁F₂: 431.11, found 431.11.

EXAMPLE 71 Preparation of4-[[4-(3,4-dichlorophenoxy)-phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8g, 27 mmol) and 3,4-dichlorophenol (2.61 g, 16 mmol). The slurry wasstirred at 95 degrees Celsius for forty-one hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP-protected hydroxamate as a white foam (4.17 g, 98%).HRMS (ES+) M+NH₄ ⁺ calculated for C₂₃H₂₅N₁O₇S₁Cl₂: 547.11, found 547.10.

Part B: To a slurry of the THP-protected hydroxamate from part A (3.5 g,6.6 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20mL) and methanol (20 mL). After fifteen minutes at ambient temperaturethe reaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue wasslurried in diethyl ether and vacuum filtration of the resultingprecipitate provided the title compound as a white solid (2.98 g, 100%).HRMS (ES+) M+NH₄ ⁺ calculated for C₁₈H₁₇N₁O₆S₁Cl₂: 463.05, found 463.05.

EXAMPLE 72 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-[(phenylmethyl)oxy]phenoxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (2.7 g, 7mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (6.84g, 21 mmol) and 4-(benzyloxy)phenol (2.8 g, 14 mmol). The slurry wasstirred at 95 degrees Celsius for six hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP-protected hydroxamate as a white foam (3.94 g, 99%).HRMS (ES+) M+NH₄ ⁺ calculated for C₃₀H₃₃N₁O₈S₁: 585.23, found 585.23.

Part B: To a slurry of the THP-protected hydroxamate from part A (1.42g, 2.5 mmol) in dioxane (6.3 mL) were added a 4N HCl dioxane solution(6.3 mL) and methanol (6.3 mL). After fifteen minutes at ambienttemperature the reaction was diluted with ethyl acetate and washed withwater, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theproduct was recrystallized (acetone/hexanes) to give the title compoundas a white solid (0.56 g, 46%). HRMS (ES+) MH+ calculated forC₂₅H₂₅N₁O₇S₁: 484.14, found 484.14.

EXAMPLE 73 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenylthio]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the title compound of Example 55 (3.1 g, 8mmol) in N,N-dimethylformamide (20 mL) were added potassium carbonate(2.21 g, 16 mmol) and p-(trifluoromethoxy)benzenethiol (2.33 g, 12mmol). The slurry was stirred at 70 degrees Celsius for two hours. Thereaction was concentrated in vacuo. The residue was taken up in ethylacetate, washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the substituted THP-protected hydroxamate as a white solid (4.4g, 98%). HRMS (ES+) M+NH₄ ⁺ calculated for C₂₄H₂₆N₁O₇S₂F₃: 579.14, found579.14.

Part B: To a slurry of the THP-protected hydroxamate from part A (4.15g, 7.4 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20mL) and methanol (20 mL). After fifteen minutes at ambient temperaturethe reaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (3.0 g, 85%). HRMS (ES+) M+NH₄ ⁺ calculated for C₁₉H₁₈N₁O₆S₂F₃:495.09, found 495.09.

EXAMPLE 74 Preparation ofphenylmethyl-[4-[[2-(hydroxyamino)-2-oxoethyl]sulfonyl]phenyl]carbamate

Part A: To a suspension of 2-(4-aminophenylthio) acetic acid (20.0 g,0.11 mol) in methanol (100 mL), cooled to zero degrees Celsius, wasslowly added thionyl chloride (24.0 mL, 0.33 mol). Additional methanol(100 mL) was added and the cooling bath was removed. The resultingmixture was heated at reflux for 2 hours. The reaction mixture was thencooled to ambient temperature and concentrated in vacuo. The residue wasdissolved in H₂O and neutralized with saturated NaHCO₃. The aqueousreaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Concentration in vacuoprovided the methyl ester sulfide as a dark purple oil (22.75 g,quantitative yield).

Part B: To a solution of the methyl ester sulfide of part A (10.0 g,50.7 mmol) in dichloromethane (100 mL) was added N-methylmorpholine(11.2 mL, 101.4 mmol), followed by N-(benzyloxycarbonyloxy)succinimide(12.6 g, 50.7 mmol). The resulting mixture was stirred at ambienttemperature overnight (about 18 hours) and then concentrated in vacuo.The residue was dissolved in ethyl acetate and then washed with H₂O, 5%KHSO₄, saturated NaCl and dried over Na₂SO₄. Concentration in vacuoprovided the benzyloxy carbamate sulfide as a dark oil (16.2 g, 96%).

Part C: To a solution of the benzyloxy carbamate sulfide of part B (16.2g, 48.7 mmol) in tetrahydrofuran (100 mL) and H₂O (10 mL) was addedOxone® (90.0 g, 146.4 mmol), and the resulting mixture was stirred atambient temperature for 16 hours. The reaction mixture was then filteredand the filtrate was concentrated in vacuo. The residue was dissolved inethyl acetate, washed with H₂O, saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provided the benzyloxy carbamate sulfone as a tansolid (15.6 g, 88%).

Part D: To a solution of the benzyloxy carbamate sulfone of part C (0.25g, 0.69 mmol) in tetrahydrofuran (3 mL) was added 50% aqueoushydroxylamine (1.5 mL). The resulting mixture was stirred at ambienttemperature for 24 hours. The mixture was then diluted with ethylacetate (30 mL), washed with H₂O, saturated NaCl and dried over Na₂SO₄.Concentration in vacuo followed by washing with hot diethyl etherprovided the title compound as a pale pink solid (0.20 g, 80%). MS MH⁺calculated for C₁₆H₁₇O₆N₂S: 365, found 365.

EXAMPLE 75 Preparation ofN-hydroxy-2-[[4-[[(phenylamino)carbonyl]amino]phenyl]sulfonyl]acetamide

Part A: Hydrogen gas was bubbled into a suspension of the benzyloxycarbamate sulfone of part C, Example 74 (13.4 g, 36.8 mmol) and 4% Pd/Cin tetrahydrofuran (100 mL). After the uptake of H₂ ceased the mixturewas purged with N₂ and then filtered through a pad of Celite® washingwith tetrahydrofuran. The filtrate was concentrated in vacuo to give theaniline as a brown solid (8.1 g, 96%).

Part B: To a suspension of the aniline of part A (0.50 g, 2.2 mmol) indichloromethane (4 mL) was added phenyl isocyanate (0.36 mL, 3.3 mmol).The mixture was stirred at ambient temperature overnight (about 18hours) and then diluted with dichloromethane (50 mL). The mixture wasthen washed with H₂O, saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the urea as awhite solid (0.59 g, 78%).

Part C: To a solution of the urea of part B (0.32 g, 0.92 mmol) intetrahydrofuran (3 mL) was added 50% aqueous hydroxylamine (1.5 mL). Theresulting mixture was stirred at ambient temperature for 24 hours. Themixture was then diluted with ethyl acetate (30 mL), washed with H₂O,saturated NaCl and dried over Na₂SO₄. Concentration in vacuo, followedby washing with hot diethyl ether provided the title compound as a palepink solid (0.24 g, 76%). MS MH⁺ calculated for C₁₅H₁₆O₅N₃S: 350, found350.

EXAMPLE 78 Preparation of5-[4-(3,4-dimethylphenoxy)phenyl]sulfonyl-N⁵-hydroxy-1,3-dimethylhexahydro-5-pyrimidinecarboxamide,dihydrochloride

Part A: To a solution of part B, Example 55 (2.00 g, 8.61 mmol) and1,3,5-trimethylhexahydro-1,3,5-triazine (1.21 mL, 8.61 mmol) in benzene(20 mL) was slowly added trifluoroacetic acid (0.66 mL, 8.61 mmol). Theresulting mixture was heated at reflux for 1 hour and then cooled toambient temperature. The mixture was then extracted with 2N HCl. Theaqueous layer was neutralized with saturated NaHCO₃ and then extractedwith diethyl ether. The organic layers were washed with saturated NaCland dried over Na₂SO₄. Concentration in vacuo provided thetetrahydropyrimidine as a clear oil (2.31 g, 81%).

Part B: To a solution of the tetrahydopyrimidine of part A (1.26 g, 3.81mmol) in N,N-dimethylformamide (5.0 mL) were added 3,4-dimethylphenol(0.559 g, 4.58 mmol) and Cs₂CO₃ (3.72 g, 11.43 mmol). The resultingmixture was heated at 90 degrees Celsius for 16 hours. After cooling toambient temperature, the reaction was diluted with H₂O and extractedwith ethyl acetate. The organic layers were washed with saturated NaCland dried over Na₂SO₄. Chromatography (on silica, ethyl acetate) gavethe biaryl ether as a pale amber oil (1.40 g, 85%).

Part C: To a solution of the biaryl ether of part B (0.936 g, 2.16 mmol)in tetrahydrofuran (5.0 mL) was added potassium trimethylsilanolate(0.360 g, 2.81 mmol). The resulting mixture was stirred at ambienttemperature for 48 hours and then the solvent was removed. The resultingresidue was dissolved in dichloromethane (5.0 mL) then,N-methylmorpholine (0.712 mL, 6.48 mmol) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.278 g, 2.38 mmol) wereadded. After stirring at ambient temperature for 10 minutes, PyBroP®(1.21 g, 2.59 mmol) was added. The resulting mixture was stirred atambient temperature overnight (about 18 hours), then diluted withdichloromethane (50 mL) and washed with H₂O. The organic layer wasremoved and washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate) provided the hydroxamate as awhite solid (0.970 g, 87%).

Part F: To a suspension of the hydroxamate of part E (0.667 y, 1.29mmol) in dioxane (3.0 mL) and methanol (1.0 mL) was added a solution of4N HCl in dioxane (3.22 mL, 12.9 mmol). After stirring at ambienttemperature for 30 minutes, the reaction mixture was concentrated invacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O/trifluoroacetic acid) provided the title compound as awhite solid (0.379 g, 58%). MS MH⁺ calculated for C₂₁H₂₈O₅N₃S: 434,found 434.

EXAMPLE 79 Preparation of4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a suspension of isonipectic acid (50.0 g, 0.39 mol) inmethanol (300 mL) cooled to zero degrees Celsius was slowly addeddropwise thionyl chloride (85.0 mL, 1.16 mol). Once the addition wascomplete the cooling bath was removed and the mixture was heated atreflux for 2 hours. After cooling to ambient temperature the reactionmixture was concentrated in vacuo. The resulting solids were suspendedin ethyl acetate and then washed with saturated NaHCO₃. The aqueouslayer was concentrated in vacuo and the resulting solids were dissolvedin hot ethyl acetate and decanted from the salts. The organic layerswere then concentrated in vacuo to give the methyl ester as a whitesolid (55.4 g, quantitative yield).

Part B: To a solution of di-tert-butyl dicarbonate (15.3 g, 70.0 mmol)in tetrahydrofuran (100 mL) was added the methyl ester of part A (10.0g, 70.0 mmol). The resulting mixture was stirred at ambient temperatureovernight (about 18 hours) and then concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexane) provided theBoc-piperidine methyl ester as a pale yellow oil (10.1 g, 59%).

Part C: To a solution of the Boc-piperidine methyl ester of part B(23.31 g, 0.096 mol) in tetrahydrofuran (500 mL), cooled to minus 40degrees Celsius, was slowly added lithium diisopropylamide (57.5 mL, 2.0M in THF, 0.115 mol). The resulting mixture was stirred at minus 40degrees Celsius for 1 hour and then at zero degrees Celsius for 30minutes. The mixture was then recooled to minus 40 degrees Celsius and asolution of the disulfide from Part A, Example 6 (24.37 g, 0.096 mol) intetrahydrofuran (60 mL) was slowly added. The resulting mixture wasslowly warmed to ambient temperature overnight (about 18 hours) and thenH₂O (200 mL) was added. The mixture was then concentrated in vacuo andthe aqueous layer was extracted with ethyl acetate. The organic layerswere washed with 0.5 M NaOH, H₂O, saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) gave the sulfide as anamber oil (28.1 g, 79%).

Part D: To a solution of the sulfide of part C (28.2 g, 0.076 mol) indichloromethane (250 mL), cooled to zero degrees Celsius, was addedm-chloroperoxy-benzoic acid (48 g, 0.152 mol). The resulting mixture wasstirred at zero degrees Celsius for 1 hour, and then at ambienttemperature for 2.5 hours. The mixture was then diluted with H₂O and 10%NH₄OH. The organic layer was washed with 10% NH₄OH, H₂O and dried overNa₂SO₄. Chromatography (on silica, ethyl acetate/hexane) provided thesulfone as a white solid (24.7 g, 81%).

Part E: To a solution of the sulfone of part D (3.00 g, 7.47 mmol) inN,N-dimethylformamide (15 mL) were added 4-chloro-3-methylphenol (1.28g, 8.96 mmol) and Cs₂CO₃ (7.30 g, 22.42 mmol). The resulting mixture washeated at 80 degrees Celsius for 8 hours. The mixture was thenconcentrated in vacuo, and the residue was partitioned between H₂O andethyl acetate. The organic layer was washed with saturated NaCl anddried over Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane) gavethe biaryl ether as a clear oil (3.26 g, 83%).

Part F: To a solution of the biaryl ether of part E (3.17 g, 6.05 mmol)in tetrahydrofuran (30 mL) was added potassium trimethylsilanolate (1.01g, 7.87 mmol) The resulting mixture was stirred at ambient temperaturefor 20 hours. Additional tetrahydrofuran (40 mL) was added and themixture was stirred at ambient temperature for 36 hours. Additionalpotassium trimethylsilanolate (0.233 g, 1.82 mmol) was added and themixture was stirred at ambient temperature for 23 hours. Thetetrahydrofuran was removed and the resulting residue was suspended indichloromethane (30 mL). To the suspension was added N-methylmorpholine(2.00 mL, 18.15 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine(0.780 g, 6.66 mmol) followed by PyBroP® (3.38 g, 7.26 mmol). Themixture was stirred at ambient temperature for 24 hours and thenconcentrated in vacuo. The residue was partitioned between H₂O and ethylacetate. The organic layer was washed with H₂O, saturated NaCl and driedover Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane) providedthe hydroxamate as an off-white foam (2.98 g, 81%).

Part G: To a solution of the hydroxamate of part F (2.98 g, 4.89 mmol)in dioxane (14 mL) and methanol (6 mL) was added a solution of 4N HCl indioxane (10 mL). The resulting mixture was stirred at ambienttemperature for 3.5 hours, then diethyl ether (40 mL) was added and theprecipitate was collected by filtration to provide the title compound asa light pink solid (2.00 g, 88%). MS MH⁺ calculated for C₁₉H₂₂O₅N₂ClS:425, found 425.

EXAMPLE 80 Preparation of4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-4-(hydroxyamino)carbonyl]-1-piperidineaceticacid, monohydrochloride

Part A: To a suspension of the title compound of Example 80 (0.250 g,0.542 mmol) in acetonitrile (4.0 mL) were added tert-butylbromoacetate(0.088 mL, 0.542 mmol) and K₂CO₃ (0.150 g, 1.08 mmol). The resultingmixture was stirred at ambient temperature for 18 hours, then filteredthrough a pad of Celite®, washing with ethyl acetate. The filtrate wasthen concentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O/trifluoroacetic acid) provided the tert-butyl ester asa white solid (0.156 g, 53%).

Part B: The tert-butyl ester of part A (0.156 g, 0.289 mmol) was treatedwith a solution of 4N HCl in dioxane (1.5 mL) and the resulting mixturewas stirred at ambient temperature for 3.5 hours at which timeadditional dioxane (2 mL) was added. After stirring at ambienttemperature for 8 hours the reaction mixture was concentrated in vacuo.The residue was treated again with a solution of 4N HCl in dioxane (1.5mL) at ambient temperature for 4 hours. Diethyl ether was added to thereaction mixture and the precipitate was collected by filtration to givethe title compound as an off-white solid (0.111 g, 74%). MS MH⁺calculated for C₂₁H₂₄O₇N₂SCl: 483, found 483.

EXAMPLE 81 Preparation of4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a suspension of the title compound of Example 79 (0.500 g,1.08 mmol) in acetonitrile (8.0 mL) were added propargyl bromide (0.126mL, 80% solution in toluene, 1.13 mmol) and K₂CO₃ (0.300 g, 2.17 mmol).The resulting mixture was stirred at ambient temperature for 24 hours,then filtered through a pad of Celite®, washing with methanol and thefiltrate was then concentrated in vacuo. Chromatography (on silica,ethyl acetate) provided the N-propargyl hydroxamate as a tan solid(0.200 g, 40%).

Part B: To a solution of the N-propargyl hydroxamate of part A (0.200 g,0.432 mmol) in acetonitrile (3.0 mL) and H₂O (0.5 mL) was addedconcentrated HCl (0.05 mL). The resulting mixture was stirred at ambienttemperature for 5 minutes and the concentrated in vacuo to provide thetitle compound as a pink solid (0.200 g, 93%). MS MH⁺ calculated forC₂₂H₂₄O₅N₂SCl: 463, found 463.

EXAMPLE 82 Preparation of4-[[4-(4-chloro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propenyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a suspension of the title compound of Example 79 (0.500 g,1.08 mmol) in acetonitrile (8.0 mL) were added allyl bromide (0.093 mL,1.08 mmol) and KCO, (0.300 g, 2.17 mmol). The resulting mixture wasstirred at ambient temperature for 22 hours. Additional allyl bromide(0.054 mL, 1M in acetonitrile, 0.054 mmol) was added and stirring wascontinued at ambient temperature for 6 hours. The resulting mixture wasfiltered through a pad of Celite®, washing with ethyl acetate and thefiltrate was concentrated in vacuo. Chromatography (on silica,methanol/ethyl acetate) provided the N-allyl hydroxamate as an off-whitesolid (0.080 g, 15%).

Part B: To a solution of the N-allyl hydroxamate of part A (0.080 g,0.172 mmol) in acetonitrile (3.0 mL) and H₂O (1.0 mL) was addedconcentrated HCl (0.05 mL). The resulting mixture was stirred at ambienttemperature for ten minutes and then concentrated in vacuo to providethe title compound as a white solid (0.100 g, quantitative yield). MSMH⁺ calculated for C₂₂H₂₆O₅N₂SCl: 465, found 465.

EXAMPLE 83 Preparation of4-[[4-(4-fluoro-3-methylphenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the sulfone of part D, Example 79 (5.00 g,12.45 mmol) in tetrahydrofuran (100 mL) was added potassiumtrimethylsilanolate (4.79 g, 37.36 mmol). The resulting mixture wasstirred at ambient temperature for 1.5 hours, diluted with H₂O anddiethyl ether (100 mL). The aqueous layer was extracted with diethylether and the combined organic layers were washed with H₂O. The aqueouslayers were combined and acidified with 2N HCl (pH=2) and then extractedwith ethyl acetate. The combined organic layers were washed withsaturated NaCl and dried over Na₂SO₄ to provide the acid as an off-whitesolid (4.61 g, 96%).

Part B: To a suspension of the acid of part A (0.830 g, 2.14 mmol) indichloromethane (10 mL) was added N-methylmorpholine (0.706 mL, 6.42mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.276 g, 2.35 mmol).After stirring at ambient temperature for 5 minutes, PyBroP® (1.20 g,2.57 mmol) was added and the resulting mixture was stirred at ambienttemperature for 19 hours. The mixture was concentrated in vacuo and theresidue was partitioned between H₂O and ethyl acetate. The aqueous layerwas further extracted with ethyl acetate and the combined organic layerswere washed with saturated NaCl and dried over Na₂SO₄. Chromatography(on silica, ethyl acetate/hexane) provided the p-fluorosulfone as awhite crystalline solid (0.993 g, 95%).

Part C: To a solution of the p-fluorosulfone of part B (0.485 g, 0.996mmol) in N,N-dimethylformamide (5 mL) were added 4-fluoro-3-methylphenol(0.133 mL, 1.20 mmol) and Cs₂CO₃ (0.973 g, 2.99 mmol). The resultingmixture was heated at 60 degrees Celsius for 17 hours. Additional4-fluoro-3-methylphenol (0.055 mL, 0.498 mmol) was added and thetemperature of the reaction mixture was increased to 80 degrees Celsiusfor 4 hours and then to 100 degrees Celsius for 3 hours. Additional4-fluoro-3-methylphenol (0.133 mL, 1.20 mmol) was added and the reactionmixture was heated at 100 degrees Celsius for 7.5 hours. AdditionalCs₂CO₃ was added and heating continued at 100 degrees Celsius for 17hours. The reaction was cooled to ambient temperature and thenconcentrated in vacuo. The residue was partitioned between H₂O and ethylacetate. The organic layer was washed with saturated NaCl and dried overNa₂SO₄. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as an off-white solid (0.490 g, 83%).

Part D: To a solution of the protected hydroxamate of part C (0.479 g,0.808 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solutionof 4N HCl in dioxane (2.02 mL, 8.08 mmol). The resulting mixture wasstirred at ambient temperature for 1.5 hours. Diethyl ether (5 mL) wasadded and the precipitate was collected by filtration to give the titlecompound as an off-white solid (0.323 g, 90%). MS MH⁺ calculated forC₁₉H₂₂O₅N₂SF: 409, found 409.

EXAMPLE 84 Preparation of4-[[4-(3-chloro-4-fluorophenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride

Part A: To a solution of the p-fluorosulfone of Part B, Example 83(0.485 g, 0.996 mmol) in N,N-dimethylformamide (5.0 mL) were added4-fluoro-3-chlorophenol (0.176 g, 1.20 mmol) and Cs₂CO₃ (0.973 g, 2.99mmol). The resulting mixture was heated at 60 degrees Celsius for 17hours, then additional 4-fluoro-3-chlorophenol (0.073 g, 0.498 mmol) wasadded and the reaction mixture was heated at 80 degrees Celsius for 24hours then increased to 90 degrees Celsius. After heating 90 degreesCelsius for 7 hours additional 4-fluoro-3-chlorophenol (0.176 g, 1.20mmol) was added and heating was continued at 90 degrees Celsius for 7.5hours. Additional Cs₂CO₃ (0.973 g, 2.99 mmol) was added and the mixturewas heated at 90 degrees Celsius for 24 hours. After cooling to ambienttemperature, the reaction mixture was concentrated in vacuo. The residuewas partitioned between H₂O and ethyl acetate. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the protected hydroxamate as anoff-white solid (0.550 g, 90%).

Part B: To a solution of the protected hydroxamate of part A (0.530 g,0.864 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solutionof 4N HCl in dioxane (2.00 mL, 8.00 mmol). The resulting mixture wasstirred at ambient temperature for 1.5 hours. Diethyl ether (5 mL) wasadded and the precipitate was collected by filtration to give the titlecompound as an off-white solid (0.377 g, 94%). MS MH⁺ calculated forC₁₉H₁₉O₅N₂SFCl: 429, found 429.

EXAMPLE 85 Preparation of4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of sulfone of part D, Example 79 (4.53 g, 11.28mmol) in N,N-dimethylformamide (20 mL) were added 4-chlorophenol (4.41g, 13.54 mmol) and Cs₂CO₃ (11.03 g, 33.85 mmol) The resulting mixturewas heated at 90 degrees Celsius for 5 hours. After cooling to ambienttemperature, the reaction mixture was concentrated in vacuo. The residuewas partitioned between H₂O and ethyl acetate. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the biaryl ether as a white solid(4.60 g, 78%).

Part B: To a solution of the biaryl ether of part A (4.57 g, 8.96 mmol)in dioxane (10 mL) was added a solution of 4N HCl in dioxane (10 mL).The resulting mixture was stirred at ambient temperature for 2.5 hoursand then additional dioxane (10 mL) was added. After stirring at ambienttemperature for 1.5 hours the mixture was concentrated in vacuo. Theresulting solid was suspended in dioxane (20 mL) and retreated with asolution of 4N HCl in dioxane (10 mL). The mixture was stirred atambient temperature for 1 hour, methanol (1 mL) was added and stirringwas continued at ambient temperature. After 1 hour, the mixture wasconcentrated in vacuo to give the amine as a white solid (4.09 g,quantitative yield).

Part C: To a suspension of the amine of part B (4.00 g. 8.96 mmol) inacetonitrile (20 mL) were added propargyl bromide (1.05 mL, 80% solutionin toluene, 9.41 mmol) and K₂CO₃ (2.60 g, 18.82 mmol). The resultingmixture was stirred at ambient temperature for 18 hours, filteredthrough a pad of Celite®, washing with ethyl acetate, and then thefiltrate was concentrated in vacuo to provide the N-propargyl amine as asticky foam (4.14 g, quantitative yield).

Part D: To a suspension of the N-propargyl amine of part C (4.14 g, 8.96mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate(1.26 g, 9.86 mmol). The resulting mixture was stirred at ambienttemperature for 17 hours and additional tetrahydrofuran (5 mL) andpotassium trimethylsilanolate (0.350 g, 2.73 mmol) were added. Afterstirring at ambient temperature for 4 hours, additional tetrahydrofuran(5 mL) was added and stirring was continued at ambient temperature for24 hours. Additional potassium trimethylsilanolate (0.115 g, 0.896 mmol)was added and the mixture was stirred at ambient temperature for 24hours, at which time, additional potassium trimethylsilanolate was addedand the resulting mixture was stirred at ambient temperature for another24 hours. The tetrahydrofuran was removed and the residue was suspendedin dichloromethane (20 mL).

To the dichloromethane suspension were added N-methylmorpholine (2.96mL, 26.9 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.15 g,9.86 mmol), followed by PyBroP® (5.01 g, 10.75 mmol). The resultingmixture was stirred at ambient temperature overnight and thenconcentrated in vacuo. The residue was partitioned between H₂O and ethylacetate. The organic layer was washed with saturated NaCl and dried overNa₂SO₄. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as an off-white foam (3.29 g, 69%).

Part E: To a solution of the protected hydroxamate of part D (3.27 g,6.13 mmol) in dioxane (21 mL) and methanol (7 mL) was added a solutionof 4N HCl in dioxane (10 mL). The resulting mixture was stirred atambient temperature for 4 hours and then diethyl ether (75 mL) wasadded. The solids were collected by filtration, washing with diethylether, to give the title compound as an off-white solid (2.95 g, 99%).MS MH⁺ calculated for C₂₁H₂₂O₅N₂SCl: 449, found 449.

EXAMPLE 86 Preparation of4-[[4-(phenylthio)phenyl]-sulfonyl]-N-hydroxy-4-piperidine-carboxamide,monohydrochloride

Part A: To a solution of the sulfone of part D, Example 79 (0.500 g,1.25 mmol) in N,N-dimethylformamide (3.0 mL) were added thiophenol(0.154 mL, 1.50 mmol) and K₂CO₃ (0.518 g, 3.75 mmol). The resultingmixture was stirred at ambient temperature for 24 hours and thenconcentrated in vacuo. The residue was partitioned between H₂O and ethylacetate. The organic layers were washed with saturated NaCl and driedover Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane) providedthe biaryl thioether as a clear sticky oil (0.480 g, 78%).

Part B: To a solution of the biaryl thioether of part A (2.01 g, 4.09mmol) in tetrahydrofuran (40 mL) was added potassium trimethylsilanolate(0.682 g, 5.31 mmol). The resulting mixture was stirred at ambienttemperature for 23 hours and then concentrated in vacuo. The residue wasthen suspended in dichloromethane (20 mL) then N-methylmorpholine (1.35mL, 12.27 mmol) and 50% aqueous hydroxylamine (0.265 mL, 4.50 mmol) wereadded, followed by PyBroP® (2.29 g, 4.91 mmol). The resulting mixturewas stirred at ambient temperature for 16 hours and then concentrated invacuo. The residue was partitioned between ethyl acetate and H₂O. Theorganic layer was washed with saturated NaCl and dried over Na₂SO₄. Aportion of the sample was subjected to reverse phase chromatography (onsilica, acetonitrile/H₂O/trifluoroacetic acid) to give the hydroxamateas an off-white solid (0.190 g).

Part C: To a solution of the hydroxamate of part B (0.181 g, 0.367 mmol)in dioxane (5 mL) and methanol (1 mL) was added a solution of 4N HCl indioxane (3 mL). The resulting mixture was stirred at ambient temperaturefor 3 hours and then concentrated in vacuo to give the title compound asan off-white solid (0.170 g, quantitative yield). MS MH⁺ calculated forC₁₉H₂₁O₄N₂S₂: 393, found 393.

EXAMPLE 87 Preparation of4-[(hydroxyamino)carbonyl]-4-[[4-(phenylthio)phenyl]sulfonyl]-1-piperidineaceticacid, monohydrochloride

Part A: To a solution of the compound of Example 86 (0.322 g, 0.751mmol) in acetonitrile (4.0 mL) were added tert-butylbromoacetate (0.121mL, 0.751 mmol) and K₂CO₃ (0.207 g, 1.50 mmol). The resulting mixturewas stirred at ambient temperature for 18 hours, filtered through a padof Celite®, washing with ethyl acetate, and the filtrate wasconcentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O/trifluoroacetic acid) provided the tert-butyl ester asan off-white solid (0.150 g, 40%).

Part B: The tert-butyl ester of part A (0.145 g, 0.286 mmol) was treatedwith absolution of 4N HCl in dioxane (3.0 mL). The resulting mixture wasstirred at ambient temperature for 7 hours, diethyl ether was added andthe precipitate was collected by filtration. Reverse phasechromatography (on silica, acetonitrile/H₂O/HCl) provided the titlecompound as an off-white solid (0.060 g, 43%). MS MH⁺ calculated forC₂₀H₂₃O₆N₂S₂: 451, found 451.

EXAMPLE 88 Preparation of4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-4-[(hydroxyamino)carbonyl]-1-piperidineaceticacid, monohydrochloride

Part A: To a suspension of 4-bromopiperidine hydrobromide (40.0 g, 0.16mol) in tetrahydrofuran (200 mL) was slowly added triethylamine (45.4mL, 0.33 mol), followed by di-tert-butyl dicarbonate (37.4 g, 0.17 mol),which was added in several portions. The resulting mixture was stirredat ambient temperature for 17 hours then filtered and concentrated invacuo. The solids were washed with hexanes and then collected byfiltration to give the Boc-piperidine compound as an amber oil (45.8 g,>100%).

Part B: To a solution of 4-fluorophenol (25.0 g, 0.20 mol) in acetone(150 mL), degassed with N₂, was added Cs₂CO₃ (79.7 g, 0.25 mol). Afterdegassing the resulting mixture with N₂ for 5 minutes, theBoc-piperidine compound of part A (43.1 g, 0.16 mol) was added. Theresulting mixture was stirred at ambient temperature for 22 hours andthen filtered through a pad of Celite®, washing with acetone. Theresidue was washed with diethyl ether and the solids were collected byfiltration to provide the sulfide as a yellow oil (47.6 g, 93%).

Part C: To a solution of the sulfide of part B (47.3 g, 0.15 mol) indichloromethane (350 mL), cooled to zero degrees Celsius, was addedm-chloroperoxy-benzoic acid (80 g, 57-86%). Additional dichloromethane(50 mL) was added and the mixture was stirred at zero degrees Celsiusfor 1 hour and then for 1.5 hours at ambient temperature. The reactionmixture was diluted with H₂O and aqueous sodium meta-bisulfite (4.0 g in50 mL) was added. The mixture was concentrated in vacuo and thenextracted with diethyl ether and ethyl acetate. The combined organiclayers were washed with 10% NH₄OH, saturated NaCl and dried over Na₂SO₄.Recrystallization from ethyl acetate provided the sulfone as a whitesolid (18.9 g, 36%).

Part D: To a solution of the sulfone of part C (8.00 g, 23.3 mmol) inN,N-dimethylformamide (40 mL) were added 4-chlorophenol (3.59 g, 27.96mmol) and K₂CO₃ (22.77 g, 69.90 mmol). The resulting mixture was heatedat 60 degrees Celsius for 4 hours and then increased to 80 degreesCelsius for 7 hours. The reaction was cooled to ambient temperature andthen concentrated in vacuo. To the residue was added H₂O (100 mL) andthe solids were collected by filtration to give the biaryl ether as anoff-white solid (10.5 g, 99%).

Part E: To a solution of the biaryl ether of part D (5.00 g, 11.1 mmol)in tetrahydrofuran (50 mL), cooled to zero degrees Celsius, was addedlithium bis(trimethylsilyl)amide (13.3 mL, 1M in tetrahydrofuran, 13.3mmol), at such a rate that the temperature of the reaction mixture neverexceeded 2 degrees Celsius. The resulting mixture was stirred at zerodegrees Celsius for 30 minutes, then dimethyl carbonate (1.40 mL, 16.6mmol) was slowly added at such a rate that the temperature of thereaction mixture never exceeded 2 degrees Celsius. The resulting mixturewas then slowly permitted to warm to ambient temperature.

After 17 hours, the reaction was recooled to zero degrees Celsius andadditional lithium bis(trimethylsilyl)amide (5.50 mL, 1M intetrahydrofuran, 5.50 mmol) was slowly added at a rate such that thetemperature of the reaction never exceeded 2 degrees Celsius. Afterstirring for 30 minutes, dimethyl carbonate (0.048 mL, 0.570 mmol) wasadded and stirring was continued at zero degrees Celsius for 45 minutes.Additional lithium bis(trimethylsilyl)amide (0.500 mL, 1M intetrahydrofuran, 0.500 mmol) was slowly added and after 1 houradditional dimethyl carbonate (0.010 mL, 0.119 mmol) was added. Afterstirring at zero degrees Celsius for 20 minutes, saturated NH₄Cl wasadded and the reaction mixture was then concentrated in vacuo. Theresidue was diluted with H₂O and extracted with ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried overNa₂SO₄. Recrystallization from methanol provided the methyl ester as awhite crystalline solid (3.56 g, 63%).

Part F: To a solution of the methyl ester of part E (3.54 g, 6.94 mmol)in dioxane (18 mL) and methanol (6 mL) was added a solution of 4N HCl indioxane (10 mL). The resulting mixture was stirred at ambienttemperature for 5 hours and then concentrated in vacuo to provide theamine as an off-white solid (3.10 g, quantitative yield).

Part G: To a solution of the amine of part F (1.50 g, 3.36 mmol) inacetonitrile (15 mL) were added tert-butylbromoacetate (0.570 mL, 3.53mmol) and K₂CO₃ (1.16 g, 8.40 mmol). The resulting mixture was stirredat ambient temperature for 3 hours, then filtered through a pad ofCelite®, washing with ethyl acetate. The filtrate was concentrated invacuo to provide the tert-butyl ester as a pale yellow oil (1.83 g,>100%).

Part H: To a solution of the tert-butyl ester of part G (1.76 g, 3.36mmol) in tetrahydrofuran (15 mL) was added potassium trimethylsilanolate(0.475 g, 3.70 mmol). The resulting mixture was stirred at ambienttemperature overnight (about 18 hours) and additional tetrahydrofuran(10 mL) was added. After stirring at ambient temperature overnight(about 18 hours), additional potassium trimethylsilanolate (0.475 g,3.70 mmol) was added. The resulting mixture was stirred at ambienttemperature for 4 hours then diluted with H₂O. The reaction mixture wasacidified (pH˜7) with 1N HCl and then concentrated in vacuo. The solidswere washed with diethyl ether and then with H₂O to provide the acid asan off-white solid (0.597 g, 32%).

Part I: To a suspension of the acid of part H (0.597 g, 1.17 mmol) indichloromethane (5 mL) was added N-methylmorpholine (0.386 mL, 3.51mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.151 g, 1.29 mmol),followed by PyBroP® (0.655 g, 1.40 mmol). The resulting mixture wasstirred at ambient temperature overnight (about 18 hours) and thenconcentrated in vacuo. The residue was partitioned between H₂O and ethylacetate. The organic layer was washed with saturated NaCl and dried overNa₂SO₄. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as a white foam (0.510 g, 72%).

Part J: The protected hydroxamate of part I (0.510 g, 0.837 mmol) wastreated with a solution of 4N HCl in dioxane (10 mL). The resultingmixture was stirred at ambient temperature for 24 hours, then diethylether (20 mL) was added and the solids were collected by filtration toprovide the title compound as a white solid (0.370 g, 87%). MS MH⁺calculated for C₂₀H₂₂O₇N₂SCl: 469, found 469.

EXAMPLE 89 Preparation of4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-1-[2-(4-morpholinyl)ethyl]-4-piperidine-carboxamide,dihydrochloride

Part A: To a solution of the amine of part F. Example 88 (1.00 g, 2.24mmol) in acetonitrile (10 mL) were added 4-(2-chloroethyl)morpholine(0.438 g, 2.35 mmol) and K₂CO₃ (1.24 g, 8.96 mmol). The resultingmixture was stirred at ambient temperature for 1.5 hours then acatalytic amount of NaI was added and stirring was continued at ambienttemperature for 21 hours. The temperature of the reaction mixture wasthen increased to 60 degrees Celsius for 29 hours. After cooling toambient temperature, the reaction mixture was filtered through a pad ofCelite®, washing with ethyl acetate. The filtrate was concentrated invacuo to provide the ester as an oily solid (1.15 g, 98%).

Part B: To a solution of the ester of part A (1.15 g, 2.20 mmol) intetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.579g, 4.51 mmol). The reaction mixture was stirred at ambient temperaturefor 4 hours then additional tetrahydrofuran (10 mL) was added andstirring was continued at ambient temperature overnight (about 16hours). The reaction mixture was diluted with H₂O (10 mL) and acidified(pH˜7) with 1N HCl. The resulting precipitate was collected byfiltration to provide the acid as a gray solid (0.753 g, 72%).

Part C: To a suspension of the acid of part B (0.750 g, 1.47 mmol) indichloromethane (7 mL) were added N-methylmorpholine (0.500 mL, 4.55mmol), and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.198 g, 1.62mmol), followed by PyBroP® (0.822 g, 1.76 mmol). The resulting mixturewas stirred at ambient temperature for 24 hours then additionalN-methylmorpholine (0.242 mL, 2.21 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.052 g, 0.441 mmol) andPyBroP® (0.343 g, 0.735 mmol) were added. The resulting mixture wasstirred at ambient temperature for 23 hours and then additionalO-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.017 g, 0.145 mmol) andPyBroP® (0.073 g, 0.157 mmol) were added. The resulting mixture wasstirred at ambient temperature overnight (about 18 hours) and thenconcentrated in vacuo. The residue was partitioned between H₂O and ethylacetate. The organic layer was washed with saturated NaCl and dried overNa₂SO₄. Chromatography (on silica, methanol/chloroform) provided theprotected hydroxamate as an off-white solid (0.750 g, 84%).

Part D: The protected hydroxamate of part C (0.730 g, 1.20 mmol) wastreated with a solution of 4N HCl in dioxane (10 mL) and methanol (1mL). The resulting mixture was stirred at ambient temperature for 1hour, then diethyl ether (20 mL) was added and the solids were collectedby filtration to provide the title compound as a pale yellow solid(0.625 g, 87%). MS MH⁺ calculated for C₂₄H₃₁O₆N₃SCl: 525, found 525.

EXAMPLE 90 Preparation of4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N⁴-hydroxy-N¹-(1-methylethyl)-1,4-piperidinedicarboxamide

Part A: To a suspension of the amine of part F, Example 88 (0.600 g,1.34 mmol) in dichloromethane (5 mL) were added triethylamine (0.411 mL,2.95 mmol) and isopropyl isocyanate (0.198 mL, 2.01 mmol). The resultingmixture was stirred at ambient temperature for 2 hours then diluted withdichloromethane (50 mL). The mixture was washed with H₂O, saturated NaCland dried over Na₂SO₄ to give the urea as an off-white solid (0.670 g,>100%).

Part B: To a solution of the urea of part A (0.640 g, 1.29 mmol) intetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.199g, 1.55 mmol). The resulting mixture was stirred at ambient temperaturefor 17 hours at which time additional potassium trimethylsilanolate(0.015 g, 0.117 mmol) was added. The resulting mixture was stirred foran additional 24 hours then the tetrahydrofuran was removed by blowingN₂ over the mixture. To a suspension of the residue in dichloromethane(5 mL) were added N-methylmorpholine (0-426 mL, 3.87 mmol) andO-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.181 g, 1.55 mmol), followedby PyBroP® (0.902 g, 1.94 mmol). The resulting mixture was stirred atambient temperature for 7 hours and then concentrated in vacuo. Theresidue was partitioned between H₂O and ethyl acetate. The organic layerwas washed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the protected hydroxamate as anoff-white solid (0.330 g, 44%).

Part C: To a solution of the protected hydroxamate of part B (0.330 g,0.569 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solutionof 4N HCl in dioxane (10 mL). The resulting mixture was stirred atambient temperature for 3.5 hours then diethyl ether was added. Thesolids were collected by filtration to give the title compound as awhite solid (0.259 g, 92%). MS MH⁺ calculated for C₂₂H₂₇O₆N₃SCl: 496,found 496.

EXAMPLE 91 Preparation of4-[(4′-chloro[1,1′-biphenyl]-4-yl)sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of 4-bromothiophenol (16.98 g, 89.80 mmol) inacetone (200 mL), degassed with N₂, was added K₂CO₃ (12.41 g, 89.80mmol). After degassing the resulting mixture with N, for 5 minutes, theBoc-piperidine compound of part A, Example 88 (21.57 g, 81.64 mmol) wasadded. The resulting mixture was stirred at ambient temperature for 19hours and then filtered through a pad of Celite®, washing with acetone.The residue was washed with diethyl ether and the solids were collectedby filtration to provide the sulfide as a green oil (31.7 g, >100%).

Part B: To a solution of the sulfide of part A (31.68 g, 81.64 mmol) indichloromethane (200 mL), cooled to zero degrees Celsius, was addedm-chloroperoxybenzoic acid (56.35 g, 50-60%, 163.28 mmol). The resultingmixture became very thick, and additional dichloromethane (100 mL) wasadded. The mixture was stirred at zero degrees Celsius for 1.5 hours andthen at ambient temperature for 1.5 hours. The reaction mixture wasdiluted with H₂O (300 mL) and aqueous sodium meta-bisulfate (8.00 g,42.08 mmol in 50 mL of H₂O) was added. The dichloromethane was removedin vacuo and the aqueous reaction mixture was extracted with ethylacetate. The combined organic layers were washed with 10% NH₄OH,saturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe sulfone as a yellow oil (33.42 g, >100%).

Part C: To a solution of the sulfone of part B (7.80 g, 19.34 mmol) intetrahydrofuran (100 mL), cooled to zero degrees Celsius, was addedlithium bis(trimethylsilyl)amide (23.8 mL, 1M in tetrahydrofuran, 23.8mmol) at such a rate that the temperature of the reaction never exceeded2 degrees Celsius. After stirring at zero degrees Celsius for 30 minutesa solution of methyl chloroformate (2.30 mL, 29.8 mmol) intetrahydrofuran (5 mL) was added at such a rate that the temperature ofthe reaction never exceeded 2 degrees Celsius. The resulting mixture wasthen slowly allowed to warm to ambient temperature. The mixture wasdiluted with saturated NH₄Cl and the tetrahydrofuran was removed invacuo. The aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the ester as ayellow solid (6.33 g, 69%).

Part D: To a solution of the ester of part C (4.74 g, 10.28 mmol) indimethoxyethane (50 mL) were added 4-chlorophenylboronic acid (1.77 g,11.30 mmol), aqueous Cs₂CO₃ (25 mL, 2.0 M, 50.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (1 g). The resulting mixturewas stirred at ambient temperature for 3 days. The reaction mixture wasfiltered through a pad of Celite®, washing with ethyl acetate, and thefiltrate was concentrated in vacuo. Chromatography (on silica, ethylacetate/hexane) provided the biphenyl compound as an off-white solid(4.16 g, 82%).

Part E: To a solution of the biphenyl compound of part D (1.50 g, 3.04mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate(0.468 g, 3.65 mmol). The resulting mixture was stirred at ambienttemperature for 1 hour, additional tetrahydrofuran (5 mL) was added andthe reaction mixture was stirred at ambient temperature overnight (about18 hours). Additional tetrahydrofuran (15 mL) was added and the mixturewas stirred for another 26 hours at ambient temperature. Additionalpotassium trimethylsilanolate (0.040 g, 0.304 mmol) was added and themixture was stirred at ambient temperature overnight (about 18 hours)and then the solvent was removed by blowing N₂ over the reactionmixture.

To a suspension of the residue in dichloromethane (20 mL) were addedN-methylmorpholine (1.00 mL, 9.12 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.427 g, 3.65 mmol), followedby PyBroP® (2.13 g, 4.56 mmol). The resulting mixture was stirred atambient temperature for 24 hours and then concentrated in vacuo. Theresidue was partitioned between H₂O and ethyl acetate. The organic layerwas washed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the protected hydroxamate as awhite solid (1.25 g, 71%).

Part F: To a solution of the protected hydroxamate of part E (1.25 g,2.16 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of4N HCl in dioxane (10 mL). The resulting mixture was stirred at ambienttemperature for 3.5 hours, then diethyl ether (20 mL) was added. Thesolids were collected by filtration to give the title compound as awhite solid (0.900 g, 97%). MS MH⁺ calculated for C₁₈H₂₀N₂SCl: 395,found 395.

EXAMPLE 92 Preparation ofN-hydroxy-4-[[4-(methylphenylamino)phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the eater of part C, Example 91 (1.00 g, 2.17mmol) in toluene (4 mL) were added N-methylaniline (0.282 mL, 2.60mmol), Cs₂CO₃ (0.990 g, 3.04 mmol),tris(dibenzylideneacetone)-dipalladium(0) (0.018 g, 0.02 mmol) and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 0.021 g,0.033 mmol). The resulting mixture was heated to 100 degrees Celsius for20 hours. After cooling to ambient temperature, diethyl ether was added,the mixture was filtered through a pad of Celite®, washing with diethylether, and the filtrate was concentrated in vacuo. Chromatography (onsilica, ethyl acetate/hexane) provided the aniline as a yellow stickygum (0.930 g, 88%).

Part B: To a solution of the aniline of part A (0.930 g, 1.90 mmol) intetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.293g, 2.28 mmol). The resulting mixture was stirred at ambient temperaturefor 19 hours and then additional potassium trimethylsilanolate (0.024 g,0.190 mmol) was added. After stirring at ambient temperature overnight(about 18 hours) the solvent was removed by blowing N₂ over the mixture.

To a suspension of the residue in dichloromethane (10 mL) were addedN-methylmorpholine (0.627 mL, 5.70 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.267 g, 2.28 mmol), followedby PyBroP® (1.33 g, 2.85 mmol). The resulting mixture was stirred atambient temperature for 2 days and then concentrated in vacuo. Theresidue was partitioned between H₂O and ethyl acetate. The organic layerwas washed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the protected hydroxamate as awhite solid (0.860 g, 79%).

Part C: To a solution of the protected hydroxamate of part B (0.890 g,1.55 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of4N HCl in dioxane (5 mL). The resulting mixture was stirred at ambienttemperature for 1 hour, then diethyl ether (15 mL) was added. The solidswere collected by filtration to give the title compound as a white solid(0.529 g, 80%). MS MH⁺ calculated for C₁₉H₂₄O₄N₃S: 390, found 390.

EXAMPLE 93 Preparation of4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a suspension of resin I (4.98 g, 5.87 mmol) in1-methyl-2-pyrrolidinone (45 mL), in a peptide flask, were added theacid of part A, Example 83 (4.55 g, 11.74 mmol),benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonim hexafluorophosphate(6.11 g, 11.74 mmol) and N-methylmorpholine (2.58 mL, 23.48 mmol). Theresulting mixture was agitated at ambient temperature for 14 hours. Theresin was then collected by filtration, the filtrate was removed and setaside, and the resin was washed with N,N-dimethylformamide, H₂O,N,N-dimethylformamide, methanol, dichloromethane and finally withdiethyl ether. The resin was dried in vacuo at ambient temperature togive the resin bound p-fluorosulfone as a yellow solid (6.72 g, 95%).

The filtrate was diluted with H₂O and extracted with ethyl acetate. Theaqueous layer was acidified (pH-2.0) with 2N HCl and then extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over Na₂SO₄. The resulting residue was dissolved in1-methyl-2-pyrrolidinone (40 mL), the above resin was added, followed byN-methylmorpholine (1.50 mL, 13.64 mmol) andbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonim hexafluorophosphate(3.05 g, 5.86 mmol). The resulting mixture was agitated at ambienttemperature for 3.5 hours. The resin was then collected by filtrationand washed with N,N-dimethylformamide, H₂O, N,N-dimethylformamide,methanol, dichloromethane and finally with diethyl ether. The resin wasdried in vacuo at ambient temperature to give the resin boundp-fluorosulfone as a pale orange solid (6.34 g, 89%). The loading (0.78mmol/g) was determined by cleaving a small portion of the resin boundp-fluorosulfone with 95% trifluoroacetic acid/H₂O.

Part B: To a suspension of the resin bound p-fluorosulfone (0.700 g,0.546 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added p-chlorophenol(0.702 g, 5.46 mmol) and Cs₂CO₃ (1.78 g, 5.46 mmol). The resultingmixture was heated to 110 degrees Celsius for 13 hours. The resin wasthen collected by filtration and washed consecutively withN,N-dimethylformamide, H₂O, N,N-dimethylformamide, 2N HCl,N,N-dimethylformamide, methanol, and dichloromethane. The resultingresin was resubjected to the above reaction conditions for 3 hours. Theresin was then collected by filtration and washed consecutively withN,N-dimethylformamide, H₂O, N,N-dimethylformamide, 2N HCl,N,N-dimethylformamide, methanol, and dichloromethane. The solid wasdried in vacuo at ambient temperature to provide the resin boundhydroxamate as an orange solid (0.692 g, 91%).

Part C: The resin bound hydroxamate of part B (0.692 g, 0.540 mmol) wastreated with 95% trifluoroacetic acid/H₂O (3 mL) for 1 hour at ambienttemperature. The resin was filtered and washed with 95% trifluoroaceticacid/H₂O (3 mL) and then dichloromethane (2×3 mL). The filtrate was thenevaporated. Reverse phase chromatography (on silica,acetonitrile/H₂O/trifluoroacetic acid) provided the hydroxamate. Theresulting solid was dissolved in acetonitrile (5 mL) and H₂O (0.5 mL)and treated with concentrated HCl. The resulting mixture was stirred atambient temperature for 5 minutes and the concentrated in vacuo toprovide the title compound as an off-white solid (0.220 g, 91%). MS MH⁺calculated for C₁₈H₂₀O₅N₂SCl: 411, found 411.

EXAMPLE 94 Preparation ofTetrahydro-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-2H-pyran-4-carboxamide

Part A: To a stirred solution of the methyl ester compound of Example55, part C, (0.96 g, 3.2 mmol) in N,N-dimethylformamide (30 mL) wasadded phenol (0.3 g, 3.2 mmol), followed by cesium carbonate (3.2 g, 10mmol). The resulting composition was heated to 70 degrees Celsius for 5hours. The solution remained at ambient temperature for 18 hours, wasdiluted with H₂O and extracted with ethyl acetate. The organic layer waswashed with half-saturated NaCl and dried over sodium sulfate. Thesolvent was removed by rotary evaporation to yield the desired phenoxycompound (1.1 g, 92%).

Part B: Sodium hydroxide (1 g, 25 mmol) was added to a solution of thephenoxy compound of part A (1.1 g, 2.9 mmol) in THF (10 mL) and ethanol(10 mL). The resulting solution was stirred at ambient temperature for 1hour. The solution was then heated to 80 degrees Celsius for 1 hour. Thesolvent was removed by rotary evaporation and the resulting sodium saltwas acidified with 1 N HCl (50 mL) and extracted with ethyl acetate. Theorganic layer was dried over Na₂SO₄. The solvent was removed by rotaryevaporation to yield the desired phenoxy carboxylic acid (1.1 g, 99%).

Part C: To a stirred solution of the phenoxy carboxylic acid of part B(1.1 g, 3 mmol) in DMF (7 mL) was added N-hydroxybenzotriazole-H₂O(0.623 g, 4.6 mmol), followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.634 g,3.3 mmol). After 10 minutes, a 50% aqueous hydroxylamine solution wasadded (2 mL, 30 mmol) and the solution was stirred at ambienttemperature for 18 hours. The solution was diluted with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with H₂O and followed by half-saturated NaCl and then dried overNa₂SO₄. Reverse phase chromatography (on silica, acetonitrile/H₂O)provided the title compound as a white solid (0.37 g, 33%). HRMS (ES⁺)MH⁺ for C₁₈H₁₉NO₆S 378.1011. Found: 378.0994.

EXAMPLE 95 Preparation ofTetrahydro-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a stirred solution under a nitrogen atmosphere of the methylester of Example 55, part C, (1.02 g, 3.4 mmol) in N,N-dimethylformamide(20 mL) was added thiophenol (0.37 g, 3.4 mmol), followed by cesiumcarbonate (3.3 g, 10.1 mmol) and the solution was heated to 70 degreesCelsius for 17 hours. The solution remained at ambient temperature for 1hour, was diluted with H₂O and extracted with ethyl acetate. The organiclayer was washed with half-saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the S-phenylcompound (0.6 g, 41%).

Part B: To a stirred solution of the S-phenyl compound of part A (0.6 g,1.4 mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (0.8 g, 20mmol). The solution was heated to 80 degrees Celsius for 1 hour. Thesolution remained at ambient temperature for 18 hours. The solvent wasremoved by rotary evaporation, the resulting sodium salt was acidifiedwith 1 N HCl (25 mL), extracted with ethyl acetate, and the organiclayer was dried over sodium sulfate. The solvent was removed by rotaryevaporation to yield the desired S-phenyl carboxylic acid (0.6 g,quantitative yield).

Part C: To a stirred solution of the S-phenyl carboxylic acid of part B(0.6 g, 1.5 mmol) in DMF (6 mL) was added N-hydroxybenzotriazole-H₂O(0.30 g, 2.2 mmol), followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.32 g,1.6 mmol). After 10 minutes, a 50% aqueous hydroxylamine solution wasadded (1.5 mL, 22 mmol) and the solution was stirred at ambienttemperature 42 hours. The solution was diluted with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with H₂O, followed by half-saturated NaCl and dried over sodiumsulfate. Reverse phase chromatography (on silica, acetonitrile/H₂O)provided the title compound as a white solid (0.15 g, 26%). HRMS (ES⁺)MH⁺ for C₁₈H₁₉NO₅S₂ 394.0783. Found: 394.0753.

EXAMPLE 96 Preparation of4-[[4-(3,4-dimethylphenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the methyl ester Example 55, part C,(1.04 g, 3.3 mmol) in N,N-dimethylformamide (30 mL) was added3,4-dimethylphenol (0.4 g, 3.3 mmol), followed by cesium carbonate (3.2g, 10 mmol). The resulting solution was heated to 88 degrees Celsius for5 hours. The solution was concentrated by rotary evaporation, dilutedwith H₂O and extracted with ethyl acetate. The organic layer dried overMgSO₄. The solvent was removed by rotary evaporation to yield thedesired dimethylphenoxy compound (1.2 g, 91%).

Part B: To a solution of the dimethylphenoxy compound of part A (1.2 g,3 mmol) in THF (10 mL) and ethanol (10 mL) was added NaOH (1 g, 25mmol). The resulting solution was heated to 80 degrees Celsius for 1hour. The solvent was removed by rotary evaporation, the resultingsodium salt was acidified with 1 N HCl (50 mL) and extracted with ethylacetate. The organic layer was dried over sodium sulfate. The solventwas removed by rotary evaporation to yield the desired dimethylphenoxycarboxylic acid (1.2 g, quantitative yield).

Part C: To a stirred solution of the dimethylphenoxy carboxylic acid ofpart B (1.2 g, 3 nmol) in DMF (7 mL) was addedN-hydroxybenzotriazole-H₂O (0.623 g, 4.6 mmol), followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.634 g,3.3 mmol). After 10 minutes, a 50% aqueous hydroxylamine solution wasadded (2 mL, 30 mmol) and the solution was stirred at ambienttemperature 18 hours. The solution was diluted with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with H₂O and followed half-saturated NaCl and dried over Na₂SO₄.Reverse phase chromatography (on silica, acetonitrile/H₂O) provided thetitle compound as a white solid (0.52 g, 43%). HRMS (ES⁺) MH⁺ forC₂₀H₂₃NO₆S 406.1324. Found: 406.1302.

EXAMPLE 97 Preparation ofTetrahydro-N-hydroxy-4-[[4-[(6-methyl-3-pyridinyl)oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a stirred solution of the methyl ester of Example 55, Part C,(1.02 g, 3.4 mmol) in N,N-dimethylformamide (20 mL) was added5-hydroxy-2-methyl-pyridine (0.54 g, 5 mmol), followed by cesiumcarbonate (3.2 g, 10 mmol). The resulting solution was heated to 70degrees Celsius for 5 hours. The solution remained at ambienttemperature for 4 days, then was diluted with H₂O and extracted withethyl acetate. The organic layer was washed with half-saturated NaCl anddried over sodium sulfate. The solvent was removed by rotary evaporationto yield a heavy oil from which the desired white methyl pyridinecompound crystallized at ambient temperature in vacuo (1.2 g, 94%).

Part B: To a solution of the methyl pyridine compound of part A (1.2 g,3.2 mmol) in THF (13 mL) was added potassium trimethylsilanoate (0.5 g,3.5 mmol). The resulting solution was stirred at ambient temperature for18 hours, during which time a gel formed. The solvent was removed byrotary evaporation to yield the desired methyl pyridine carboxylic acid(1.4 g, quantitative yield).

Part C: To a stirred solution of the methyl pyridine carboxylic acid ofpart B (1.4 g, 3.2 mmol) in methylene chloride (10 mL) was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.79 g, 3.8mmol), followed by 4-methylmorpholine (0.97 g, 9.6 mmol), followed byO-tetrahydro-2H-pyran-yl-hydroxylamine (0.41 g, 3.5 mmol) and thesolution was stirred at ambient temperature for 1.5 hours. The solutionwas filtered to remove a precipitate and the solvent was removed byrotary evaporation. Chromatography (on silica, ethyl acetate/hexane)provided the O-tetrahydropyran methyl pyridine as a white solid (1.48 g,97%).

Part D: Methanol (3 mL) was added to a stirred solution of theO-tetrahydropyran methyl pyridine of part C (1.48 g, 3.1 mmol) in 4 NHCl in dioxane (5 mL). The solution was stirred at ambient temperaturefor 3 hours and poured into ethyl ether. The resulting precipitate wascollected by vacuum filtration. Reverse phase chromatography (on silica,acetonitrile/H₂O/HCl) provided the title compound as a white solid (0.64g, 53%). HRMS (ES⁺) MH⁺ for C₁₈H₂₀N₂O₆S 393.1120. Found: 393.1110.

EXAMPLE 98 Preparation ofTetrahydro-N-hydroxy-4-[[4-[(6-methyl-2-pyridinyl)oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a stirred solution of the methyl ester of Example 55, part C,(1.0 g, 3.3 mmol) in N,N-dimethylformamide (20 mL) was added2-hydroxy-6-methyl-pyridine (0.54 g, 5 mmol), followed by cesiumcarbonate (3.2 g, 10 mmol). The resulting solution was heated to 70degrees Celsius for 5 hours. The solution remained at ambienttemperature for 11 hours, at which time additional2-hydroxy-6-methyl-pyridine (0.3 g, 2.7 mmol) was added to the stirredsolution and the resulting solution was heated to 70 degrees Celsius for3 hours. The solution was concentrated by rotary evaporation, dilutedwith saturated NaCl in H₂O and extracted with ethyl acetate. The organiclayer was dried over sodium sulfate. The solvent was removed by rotaryevaporation and chromatography (on silica, ethyl acetate/methanol)provided the desired methyl pyridine as a white solid (0.63 g, 49%).

Part B: To a solution of the methyl pyridine compound of part A (0.63 g,1.6 mmol) in THF (13 mL) was added potassium trimethylsilanoate (0.5 g,3.5 mmol). The resulting solution was stirred at ambient temperature for18 hours. The precipitate that formed was removed by filtration, washedwith methylene chloride and dried in vacuo to provide the methylpyridine carboxylic acid potassium salt (0.4 g, 55%).

Part C: To a stirred solution of the methyl pyridine carboxylic acidpotassium salt of part B (0.4 g, 0.9 mmol) in N,N-dimethylformamide (5mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate(0.5 g, 1 mmol), followed by 4-methylmorpholine (0.27 g, 2.6 mmol),followed by a 50% aqueous hydroxylamine solution (0.6 mL, 9 mmol). Theresulting solution was stirred at ambient temperature 32 hours. Thesolution was concentrated by rotary evaporation and reverse phasechromatography (on silica, acetonitrile/H₂O) provided the title compoundas a white solid (0.162 g, 47%). HRMS (ES⁺) MH⁺ for C₁₈H₂₀O₆S 393.1120.Found: 393.1119.

EXAMPLE 99 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(1H-imidazol-1-yl)phenoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a solution of the THP pyranfluoro compound of Example 55,part C, (2.0 g, 5.2 mmol) in N,N-dimethylacetamide (6 mL) was added4-(1,3-imidazole)phenol (12.9 g, 33.3 mmol), followed by cesiumcarbonate (32.5 g, 99.9 mmol). The reaction was heated at 65 degreesCelsius for twelve hours. Removing the dimethylacetamide in vacuoafforded a brown solid. Reverse phase chromatography (on silica,acetonitrile/water) gave the THP-protected product in solution.

Part B: A solution of 10% HCl_(aq) (100 mL) was slowly added to thesolution of the crude THP-protected product from A in acetonitrile/water(100 mL). After stirring overnight (about 18 hours), the acetonitrilewas removed. The resultant precipitate was collected, giving the titlecompound as a brown solid (6.0 g, 41%). MS (FAB) M⁺H calculated forC₂₁₈H₂₁N₃O₆S₁: 444, found 444.

EXAMPLE 100 Preparation of4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyranfluoro compound of Example55, Part C, (2.9 g, 7.5 mmol) in N,N-dimethylformamide (1s mL) was addedp-chloro-phenol (1.93 g, 15 mmol), followed by cesium carbonate (7.3 g,22.5 mmol). The resulting composition was heated to 90 degrees Celsiusfor 1.5 hours. The solution remained at ambient temperature for 18 hourswith stirring, and dimethylformamide (20 mL) was added to the stirredsolution, followed by cesium carbonate (2 g, 6.2 mmol). The resultingcomposition was heated to 95 degrees Celsius for 3 hours. The solutionthen remained at ambient temperature 20 hours, at which time it wasdiluted with H₂O and extracted with ethyl acetate. The organic layer waswashed with half-saturated NaCl and dried over sodium sulfate. Thesolvent was removed by rotary evaporation. Chromatography (on silica,ethyl acetate/hexane) provided the p-chloro phenoxyphenyl THP-protectedhydroxamate compound (2.9 g, 78%).

Part B: To a solution of the p-chloro phenoxyphenyl THP-protectedhydroxamate compound of part A (2.9 g, 5.7 mmol) in dioxane (5 mL) wasadded 4N HCl in dioxane (5 mL, 20 mmol), followed by methanol (7.5 mL).The resulting solution was stirred at ambient temperature for 1 hour.The solvent was removed by rotary evaporation. Reverse phasechromatography (on silica, acetonitrile/H₂O) provided the title compoundas a white solid (1.35 g, 58%). MS (FAB) MH⁺ for C₁₈H₁₈NO₆SCl 412.Found: 412.

EXAMPLE 101 Preparation of4-[[4-(3-chlorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyranfluoro compound of Example55, Part C, (5.0 g, 13 mmol) in N,N-dimethylformamide (20 mL) was addedp-chloro-phenol (5 g, 39 mmol), followed by cesium carbonate (17 g, 52mmol). The resulting solution was heated to 95 degrees Celsius for 7hours. The solution was maintained at ambient temperature for 7 hours,diluted with H₂O and extracted with ethyl acetate. The organic layer waswashed with half-saturated NaCl and dried over sodium sulfate. Thesolution was concentrated by rotary evaporation. Chromatography (onsilica, ethyl acetate/hexane) provided the m-chloro phenoxyphenylTHP-protected hydroxamate compound (5.2 g, 82%).

Part B: To a solution of the m-chloro phenoxyphenyl THP-protectedhydroxamate compound of part A (5.2 g, 10 mmol) in dioxane (5 mL) wasadded 4N HCl in dioxane (5 mL, 20 mmol), followed by methanol (10 mL).The resulting solution was stirred at ambient temperature for 1 hour.The solvent was removed by rotary evaporation to provide the titlecompound as a white solid (3.4 g, 79%). HRMS (ES⁺) M+NH₄ ⁺ forC₁₈H₁₈NO₆SCl 429.0887. Found: 429.0880.

EXAMPLE 102 Preparation of methyl4-[4-[(tetrahydro-4-[(hydroxyamino)carbonyl]-2H-pyran-4-yl]sulfonyl]phenoxylbenzenepronanoate

Part A: To a stirred solution of the THP pyranfluoro compound of Example55, part C, (5.0 g, 13 mmol) in N,N-dimethylformamide (45 mL) was addedmethyl 3-(4-hydroxyphenyl)-propanoate (7 g, 39 mmol), followed by cesiumcarbonate (17 g, 52 mmol). The resulting composition was heated to 95degrees Celsius for 7 hours. The solution then remained at ambienttemperature for 7 hours. The solution was thereafter diluted with H₂Oand extracted with ethyl acetate. The organic layer was washed withhalf-saturated NaCl and dried over sodium sulfate. The solution wasconcentrated by rotary evaporation. Chromatography (on silica, ethylacetate/hexane) provided the methyl propanoate phenoxyphenylTAP-protected hydroxamate compound (5.6 g, 79%).

Part B: To a solution of the methyl propanoate phenoxyphenylTHP-protected hydroxamate compound of part A (5.6 g, 10 mmol) inmethanol (5 mL) was added 4N HCl in dioxane (5 mL, 20 mmol). Theresulting solution was stirred at ambient temperature for 0.5 hours. Thesolvent was removed by rotary evaporation. The residue was dissolved inmethylene chloride/ethyl acetate and the compound precipitated withhexane. The precipitate was washed with hexane and dried in vacuo toprovide the title compound as a white solid (3.8 g, 80%). HRMS (ES⁺) M⁺for C₂₂H₂₅NO₈S 464.138. Found: 464.135.

EXAMPLE 103 Preparation of4-[[4-[(4-fluorophenyl)thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution under a nitrogen atmosphere of the THPpyranfluoro compound of Example 55, part C, (2.9 g, 7.5 mmol) inN,N-dimethylformamide (25 mL) was added cesium carbonate (4.9 g, 15mmol), followed by 4-fluoro-thiophenol (1.9 g, 15 mmol). The resultingcomposition was heated to 95 degrees Celsius for 7 hours. Cesiumcarbonate was added (1.2 g, 3.8 mmol) after 1 hour of heating and againat two hours. The solution remained at ambient temperature for 9 hours,was concentrated by rotary evaporation, diluted with H₂O containing 30%brine and extracted with ethyl acetate. The organic layer was washedwith half-saturated NaCl and dried over sodium sulfate. The solution wasconcentrated by rotary evaporation. Chromatography (on silica, ethylacetate/hexane) followed by reverse phase chromatography(acetonitrile/H₂O) provided the p-fluoro-phenyl-S-phenyl THP-protectedhydroxamate compound (1.9 g, 55%).

Part B: To a solution of the p-fluoro-phenyl-S-phenyl THP-protectedhydroxamate compound of part A (1.9 g, 4 mmol) in methanol (5 mL) wasadded 4N HCl in dioxane (5 mL, 20 mmol. The resulting solution wasstirred at ambient temperature for 0.5 hours. The solvent was removed byrotary evaporation, the residue was dissolved in methylene chloride andprecipitated with hexane. The precipitate was and dried in vacuo toprovide the title compound as a white solid (1.5 g, 89%). HRMS (ES⁺)M+NH₄ ⁺ for C₁₈H₁₈O₅S₂F 429.0954. Found: 429.0948.

EXAMPLE 104 Preparation ofTetrahydro-N-hydroxy-4-[[4-(4-pyridinylthio)phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a stirred solution of the THP pyranfluoro compound of Example55, Part C, (2.9 g, 7.5 mmol) in N,N-dimethylformamide (20 mL) was addedpotassium carbonate (2.6 g, 19 mmol), followed by 4-mercaptopyridine(1.7 g, 15 mmol). The resulting composition was heated to 75 degreesCelsius for 5 hours. Potassium carbonate was added (0.26 g, 1.9 mmol)after 1 hour of heating and again at two hours. The solution remained atambient temperature for 14 hours. The solution was concentrated byrotary evaporation, diluted with H₂O containing 30% brine and extractedwith ethyl acetate. The organic layer was washed with half-saturatedNaCl and dried over Na₂SO₄. The solution was concentrated by rotaryevaporation. Chromatography (on silica, ethyl acetate/hexane) providedthe mercaptopyridine THP-protected hydroxamate compound (1.2 g, 33%).

Part B: To a solution of the mercaptopyridine THP-protected hydroxamatecompound of part A (1.2 g, 2.5 mmol) in acetonitrile (20 mL) was added12.5 N HCl (0.4 mL, 5 mmol), followed by methanol (3 mL). The resultingsolution was stirred at ambient temperature for 1 hour. The precipitatewas filtered, washed with methanol followed by ethyl ether and dried invacuo to provide the title compound as a white solid (0.92 g, 86%). HRMS(ES⁺) M+NH₄ ⁺ for C₁₇H₁₈N₂O₅S₂ 395.0735. Found: 395.0734.

EXAMPLE 105 Preparation of4-[4-[[tetrahydro-4-[(hydroxyamino)carbonyl]-2H-pyran-4-yl]sulfonyl]phenoxy]benzenenpropanoicacid

Part A: To a stirred solution of the title compound of Example 102 (0.1g, 0.2 mmol) in methanol (0.5 mL) was added aqueous 1 M Li(OH)₂ (0.43mL, 0.43 mmol). After standing at ambient temperature 24 hours, thesolution was refluxed 20 hours. The solution was lyophilized to drynessand reverse phase chromatography provided the title compound as a whitesolid (9 mg, 9%). MS (FAB) M+Li⁺ for C₂₁H₂₃NO₈S 456. Found: 456.

EXAMPLE 106 Preparation ofTetrahydro-N-hydroxy-4-[[4-[[1-(2-propynyl)-4-piperidinyl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide,monohydrochloride

Part A: To a heat dried three-neck flask under a nitrogen atmosphere wasadded NaH (1.59 g of 60%, 40 mmol) slurried in N,N-dimethylformamide (50mL). The slurry was chilled to zero degrees Celsius using an ice bathand N-Boc-4-hydroxy piperidine was added (8 g, 40 mmol) followed by aN,N-dimethylformamide rinse (10 mL). The ice bath was removed and thestirred solution permitted to reach ambient temperature over two hours.The stirred solution was again chilled to zero degrees Celsius and themethyl ester compound of Example 55, part C, (10 g, 33 mmol) dissolvedin N,N-dimethylformamide (40 mL) was added. The ice bath was removed andthe solution stirred at ambient temperature 48 hours. The solution wasconcentrated by rotary evaporation. The solution was diluted with H₂Oand extracted with ethyl acetate. The organic layer was dried oversodium sulfate. After chromatography (on silica, ethylacetate/hexane/methanol), the crude N-Boc methyl ester was treated with1 N HCl in methanol. The solvent was removed by rotary evaporation. Theresidue was then dissolved in acetonitrile (21 mL) to which H₂O wasadded (21 mLs). Reverse phase chromatography (on silica,acetonitrile/H₂O) afforded the purified piperidine methyl ester as theHCl salt (4.9 g, 35%).

Part B: To a stirred suspension of the piperidine methyl ester HCl saltof part A (1.8 g, 4 mmol) in acetonitrile (24 mL) and was addedpotassium carbonate (1.8 g, 13 mmol), followed by propargyl bromide(0.58 mL of 80% solution, 5.2 mmol). The mixture was stirred at ambienttemperature for 18 hours. The solution was concentrated by rotaryevaporation, diluted with H₂O and extracted with ethyl acetate. Theorganic layer was dried over Na₂SO₄ and concentrated by rotaryevaporation. Chromatography (on silica, methylene chloride/methanol)provided the propargyl piperidine methyl ester compound (1.1 g, 63%).

Part C: To a solution of the propargyl piperidine methyl ester compoundof part B (1.1 g, 2.7 mmol) in THF (3 mL) was added potassiumtrimethylsilanoate (0.57 g, 4 mmol). After 5 minutes, THF was added (12mL), followed by a second addition of THF (15 mL) after 10 more minutes.The resulting solution was stirred at ambient temperature for 18 hours,during which a gel formed. The solvent was removed by rotaryevaporation, and the residue was diluted with H₂O and washed with ethylacetate. The aqueous layer was acidified and chromatographed (on silica,acetonitrile/H₂O) to provide the desired propargyl piperidine carboxylicacid after lyophilization (0.64 g, 59%).

Part D: To a stirred solution of propargyl piperidine carboxylic acid ofpart C (0.64 g, 1.6 mmol) in N,N-dimethylformamide (5 mL) was added1-hydroxybenzotriazole (0.3 g, 2.3 mmol), followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.33 g,1.7 mmol), followed by O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.57 g,4.8 mmol). The solution was stirred at ambient temperature 42 hours,concentrated by rotary evaporation, diluted with H₂O and extracted withethyl acetate. The organic layer was washed with saturated sodiumbicarbonate, followed by brine and dried over Na₂SO₄. The solution wasconcentrated by rotary evaporation and chromatographed on reverse phase(on silica, acetonitrile/H₂O) to provide the title compound as a whitesolid upon lyophilization (0.2 g, 30%). HRMS (ES⁺) MH⁺ for C₂₀H₂₆N₂O₆S423.159. Found: 423.159.

EXAMPLE 107 Preparation of4-[[4-[(1-acetyl-4-piperidinyl)oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: Acetic anhydride (1.7 g, 16 mmol) was added to a stirredsuspension of the piperidine methyl ester HCl salt of Example 106, partA, (1.8 g, 4 mmol) in pyridine (2 mL). The mixture was stirred atambient temperature for 20 minutes. The solution was concentrated byrotary evaporation and chromatographed (on silica, ethylacetate/methanol) to provide the acetyl piperidine methyl ester compound(1.5 g, 83%).

Part B: To a solution of the acetyl piperidine methyl ester compound ofpart A (1.5 g, 3.3 mmol) in THF (5 mL) was added potassium 15trimethylsilanoate (0.86 g, 6 mmol). After 5 minutes, THF was added (15mL), followed by a second addition of THF (15 mL) after 10 more minutes.The resulting solution was stirred at ambient temperature for 18 hours.The precipitate was isolated by filtration to provide the desired acetylpiperidine carboxylic acid (1.5 g, 98).

Part C: To a stirred solution of acetyl piperidine carboxylic acid ofpart B (0.9 g, 2 mmol) in dimethylacetamide (5 mL) was addedbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1 g, 2.3 mmol),followed by 4-methylmorpholine (0.6 g, 6 mmol), followed by aqueousO-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.5 mL, 23 mmol) and thesolution was stirred at ambient temperature 48 hours. Reverse-phasechromatography (on silica, H₂O/acetonitrile) provided title compound asa white solid (0.1 g, 12%). MS (FAB) MH⁺ for C₁₉H₂₆N₂O₇S 427. Found:427.

EXAMPLE 108 Preparation of4-[[4-(3-chloro-4-fluorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a stirred solution of the THP pyranfluoro compound of Example55, part C, (3.2 g, 7.7 mmol) in N,N-dimethylacetamide (15 mL) was addedthe 3-chloro-4-fluorophenol (1.7 mL, 12 mmol), followed by cesiumcarbonate (5 g, 15.5 mmol). The reaction was heated at 95 degreesCelsius for 2 hours. Cesium carbonate (2.5 g, 8 mmol) was added, and thereaction was heated at 95 degrees Celsius for 6 hours. The solutionremained at ambient temperature for 8 hours. The crude reaction was thenfiltered to remove the cesium chloride and precipitated product. Thefilter cake was suspended in H₂O and acidified with HCl to pH=6. Afterfoaming ceased, the precipitate was removed by filtration, washed withH₂O, dissolved in H₂O/acetonitrile and chromatographed over a reversephase HPLC column (H₂O/acetonitrile) to give the3-chloro-4-fluorophenoxy THP-protected hydroxamate (1.4 g, 35%).

Part B: To a stirred solution of the 3-chloro-4-fluoro phenoxyTHP-protected hydroxamate from part A (1.4 g, 2.7 mmol) in acetonitrile(10 mL) was added 1N aqueous HCl (10 mL). The solution was stirred atambient temperature for 1 hour. The acetonitrile was evaporated off atambient temperature under a steady stream of nitrogen until a heavyprecipitate formed. The precipitate was filtered and the cake was washedwith H₂O followed by diethyl ether and dried under vacuum, giving thetitle compound as a white solid (12.5 g, 96%). The compound wasrecrystallized from acetone/hexane, giving white crystals (10.9 g, 86%).HRMS (ES) M+NH₄ ⁺ for C₁₈H₁₉NO₆SFCl 447.079. Found: 447.080.

EXAMPLE 109 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-phenoxy)phenyl]sulfonyl2H-thiopyran-4-carboxamide

Part A: To a solution of the methylester thiopyran compound of Part C,Example 50 (MW 318, 3 g, 1.0 equivalents) in N,N-dimethylacetamide (DMA;40 mL) were added cesium carbonate (12 g, 1.5 equivalents) and phenol(1.5 g). The mixture was heated to 95 degrees Celsius for 6 hours. Afterthe reaction was cooled to ambient temperature, the reaction mixture wasfiltered and the N,N-dimethylacetamide was then removed via rotaryevaporation. The residue was dissolved in 10% aqueous HCl (100 mL) andextracted with ethyl acetate (2×). The ethyl acetate extract was driedover sodium sulfate and removed under reduced pressure to give an oil.The oil was purified on silica gel to give 2 g of methyl ester. The ¹HNMR, MS, and HPLC were consistent with the desired compound.

Part B: To a solution of the methyl ester compound of Part A (MW 392, 2g) in THF (20 mL) was added potassium trimethylsilanoate (MW 128,1.6 g,1.2 equivalents). The mixture stirred 2-3 hours at ambient temperatureuntil a solid precipitate developed. After the hydrolysis was complete,N-methylmorpholine (2 mL) was added followed by PyBrop (2.3 g, 1.2equivalents). The solution was stirred for 10 minutes, then aqueoushydroxylamine was added and stirring for an additional 2 hours. Aftercomplete reaction (2 hours) the solvent was removed via rotaryevaporation. The residue was dissolved in water/acetonitrile, madeacidic with TFA (pH=2), then purified on prep RPHPLC to give 1 g thetitle compound as a white solid. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound. MS (CI) M+H calculated forC₁₈H₁₉NO₅S₂: 393, found 393.

EXAMPLE 110 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-phenoxy)phenyl]sulfonyl 2H-sulfonylpyran-4-carboxamide

Part A: Water (50 mL) was added to a solution of the compound of Example109, part A, (2 g) in tetrahydrofuran (50 mL). To this vigorouslystirred mixture was added Oxone® (8 g, 3 equivalents). The course of thereaction was monitored by RPHPLC. After 3 hours, water was added and theproduct was extracted with ethyl acetate (100 mL, 2×). The ethyl acetatewas dried over sodium sulfate. After solvent was removed via reducedpressure, 1.8 g of the phenoxy methyl ester compound was obtained as awhite solid. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound.

Part B: To a solution of the phenoxy methyl ester compound of part A (MW590, 2 g) in tetrahydrofuran (20 mL) was added potassiumtrimethylsilanoate (MW 128,1.2 g, 1.2 equivalents). The mixture wasstirred 2-3 hours until a solid precipitate developed. After thehydrolysis was complete, N-methylmorpholine (2 mL) was added followed byPyBrop (2.3 g, 1.2 equivalents). The solution was stirred for 10 minutesthen aqueous hydroxylamine was added and with stirring for an additional2 hours. After complete reaction, (2 hours) the solvent was removed viarotary evaporation. The residue was dissolved in water/acetonitrile,made acidic with trifluoroacetic acid (pH=2), then purified on prepRPHPLC to give 500 mg of the title compound as a white solid. The ¹HNMR, MS, and HPLC were consistent with the desired compound. MS (CI) M+Hcalculated for C₁₈H₁₉NO₇S₂: 425, found 425.

EXAMPLE 111 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-phenoxy)phenyl]sulfonyl2H-sulfoxylpyran-4-carboxamide

Part A: To a solution of methyl ester of Example 109, part A, (2 g) inacetic acid/water (25/5 mL) was added hydrogen peroxide (2 mL, 30%solution). The course of this vigorously stirred solution was monitoredby RPHPLC. After 3 hours, water was added and the product was extractedwith ethyl acetate (100 mL, 2×). The ethyl acetate was dried over sodiumsulfate. After solvent was removed via reduced pressure, 2.1 grams ofthe methylester sulfoxidepyran Phenyl-O-phenyl compound was obtained asa white solid. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound.

Part B: To a solution of the methylester sulfoxidepyran Phenyl-O-phenylcompound of Part A (MW 578, 1.8 g) in tetrahydrofuran (25 mL) was addedpotassium trimethylsilanoate (MW 128, 1.2 g, 1.2 equivalents). Themixture was stirred 2-3 hours until a solid precipitate developed. Afterthe hydrolysis was complete, N-methyl morpholine (2 mL) was addedfollowed by PyBrop (2.3 g, 1.2 equivalents). The solution was stirredfor 10 minutes then aqueous hydroxylamine was added, with stirring foran additional 2 hours. After complete reaction (12 hours) the solventwas removed via rotary evaporation. The residue was dissolved inwater/acetonitrile, made acidic with trifluoroacetic acid (pH=2), thenpurified on prep RPHPLC to give 500 milligrams of the title compound asa white solid. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound. MS (CI) M+H calculated for C₁₈H₁₉NO₆S₂: 409, found 409.

EXAMPLE 112 Preparation oftetrahydro-N-hydroxy-4-[[4-(1-acetyl-4-(4-piperazinephenoxy)phenyl]sulfonyl2H-thiopyran-4-carboxamide

Part A: To a solution of the methylester thiopyran compound of Example50, part C, (MW 318, 5 g, 1.0 equivalents) in N,N-dimethylacetamide (70mL) were added cesium carbonate (MW 5.5 g, 1.5 equivalents),tetrabutylammonium fluoride (2 mL, 2 M in THF) and1-acetyl-4-(4-hydroxyphenyl)piperazine (4.9 g). The mixture was stirredand heated at 90 degrees Celsius for 6 hours. The reaction mixture wasfiltered and the N,N-dimethylacetamide was then removed via rotaryevaporation. The residue was dissolved in water (100 mL) and extractedwith ethyl acetate (2×). The ethyl acetate was dried over sodium sulfateand removed under reduced pressure to give an oil. The oil was purifiedon silica gel to give 3 g of methyl ester. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound.

Step B: To a solution of the methyl ester compound of Part A (MW 433, 3g) in tetrahydrofuran (50 mL) was added potassium trimethylsilanoate (MW128, 0.9 g, 1.2 equivalents). The mixture was stirred 2-3 hours until asolid precipitate developed. After the hydrolysis was complete N-methylmorpholine (2 mL) was added followed by PyBrop (3.5 g, 1.2 equivalents).The solution was stirred for 10 minutes then aqueous hydroxylamine wasadded with stirring for an additional 2 hours. After complete reaction(2 hours) the solvent was removed via rotary evaporation. The residuewas dissolved in water/acetonitrile, made acidic with trifluoroaceticacid (pH=2), then purified on prep RPHPLC to give 1.2 g of the titlecompound as a white solid. The ¹H NMR, MS, and HPLC were consistent withthe desired compound. MS (CI) M+H calculated for C₂₄H₂₉N₃O₆S₂: 519,found 519.

EXAMPLE 113 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-thiophenoxy)phenyl]sulfonyl2H-thiopyran-4-carboxamide

Part A: To a solution of the methylester thiopyran compound of Example50, part C, (5 g.) in acetic acid (40 mL) was added water/hydrogenperoxide (8 mL, 4 mL/4 mL, 30% solution). The course of this vigorouslystirred solution was monitored by RPHPLC. After 3 hours at ambienttemperature, water was added and the product was extracted with ethylacetate (100 mL, 2×). The ethyl acetate was dried over sodium sulfate.After solvent was removed via reduced pressure 4.5 g of the methylestersulfoxidepyran Ph-p-F was obtained as a white solid. The ¹H NMR, MS, andHPLC were consistent with the desired compound.

Part B: To a solution of the methylester sulfoxidepyran Ph-p-F of Part A(MW 318, 5 g, 1.0 equivalents) in DMA (70 mL) were added cesiumcarbonate (MW 4.5 g, 1.1 equivalents) and thiophenol (1.5 g, 1.05equivalents). The mixture was stirred 2 hours at room temperature. Thereaction mixture was filtered and the N,N-dimethylacetamide was thenremoved via rotary evaporation. The residue was dissolved in water (100mL) and extracted with ethyl acetate (2×). The ethyl acetate was driedover sodium sulfate and removed under reduced pressure to give an oil.The oil was purified on prep RPHPLC to give 2 g of methyl estersulfoxidepyran Phenyl-S-Ph compound. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound.

Part C: To a solution of the methylester sulfoxidepyran Phenyl-S-Ph ofPart B (MW 590, 5 g) in tetrahydrofuran (100 mL) was added potassiumtrimethylsilanoate (MW 128,1.5 g, 2 equivalents). The mixture wasstirred 2-3 hours at ambient temperature until a solid precipitatedeveloped. After the hydrolysis was complete. N-methyl morpholine (6 mL)was added followed by PyBrop (4 g, 1.1 equivalents). The solution wasstirred for 10 minutes then aqueous hydroxylamine was added withstirring for an additional 2 hours. After complete reaction (12 hours),the solvent was removed via rotary evaporation. The residue wasdissolved in water/acetonitrile, made acidic with trifluoroacetic acid(pH=2), then purified on prep RPHPLC to give 1.9 g of the title compoundas a white solid. The ¹H NMR, MS, and HPLC were consistent with thedesired compound. MS (CI) M+H calculated for C₁₈H₁₉NO₅S₃: 425, found425.

EXAMPLE 114 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(4-hydroxyphenyl)thiophenoxy)phenyl]sulfonyl2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of Example 50 (MW 402, 5 g,1.0 equivalent) in N,N-dimethylacetamide (70 mL) was added the4-hydroxythiophenol (MW 126, 1.6 g, 1.3 equivalents) followed bypotassium carbonate (MW 138, 5 g, 2.0 equivalents). The reaction washeated at 65 degrees Celsius for 3 hours, until HPLC indicated thereaction had finished. The reaction mixture was filtered, theN,N-dimethylacetamide was removed in vacuo. The residue was dissolved inwater (100 mL) and extracted with ethyl acetate (2×). The ethyl acetatewas dried over sodium sulfate and removed under reduced pressure to givethe p-OH thiophenoxy compound as a crude oil. The ¹H NMR, MS, and HPLCwere consistent with the desired compound.

Part B: The crude p-OH thiophenoxy compound from Part A was stirred inHCl/dioxane (50 mL) for 2 hours. The solvent was removed and the residuewas dried and dissolved in water/acetonitrile, made acidic withtrifluoroacetic acid (pH=2), then purified on prep RPHPLC to give 2.1 gof the title compound as a yellow solid. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound. MS (CI) M+H calculated forC₁₈H₁₉NO₅S₃: 425, found 425.

EXAMPLE 115 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-aminophenyl)thiophenoxy]phenyl]sulfonyl2H-thiopyran-4-carboxamide

Part A: To a solution of the title compound of Example 50 (MW 402, 5 g,1.0 equivalents) in N,N-dimethylacetamide (70 mL) was added the4-aminothiophenol (MW 126, 1.6 g, 1.3 equivalents) followed by potassiumcarbonate (MW 138, 5 g, 2.0 equivalents). The reaction was heated at 65°C. for 3 hours, until HPLC indicated the reaction had finished. Thereaction mixture was filtered, and the N,N-dimethylacetamide was removedin vacuo. The residue was dissolved in water (100 mL) and extracted withethyl acetate (2×). The ethyl acetate was dried over sodium sulfate andremoved under reduced pressure to give the p-NH₂ thiophenoxy compound asa crude oil. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound.

Part B: The crude p-NH₂ thiophenoxy compound of Part A was stirred inHCl/dioxane (50 mL) for 2 hours. The solvent was removed and the residuewas dried and dissolved in water/acetonitrile, made acidic withtrifluoroacetic acid (pH=2), then purified on prep RPHPLC to give 2.1 gof the title compound as a yellow solid. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound. MS (CI) M+H calculated forC₁₈H₂₀N₂O₄S, C₂HF₃O₂: 538, found 538.

EXAMPLE 116 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-tyramine)phenoxy]phenyl]sulfonyl2H-thiopyran-4-carboxamide

Step A: To a solution of title compound of Example 50 (MW 402, 5 g, 1.0equivalents) in N,N-dimethylacetamide (50 mL) was added the trypamine (3g, 2 equivalents), followed by cesium carbonate (10 g, 2.0 equivalents).The reaction was heated at 95 degrees Celsius for 5 hours, until HPLCindicated the reaction had finished. The reaction mixture was filtered,the N,N-dimethylacetamide was removed in vacuo. The solvent was removedand the residue was dried and dissolved in water/acetonitrile, madeacidic with trifluoroacetic acid (TFA; pH=2), then purified on prepRPHPLC to give 2.5 g of the crude methyl ester as a yellow solid. The ¹HNMR, MS, and HPLC were consistent with the desired compound.

Step B: The crude methyl ester from reaction Step A was stirred inaqueous HCl (50 mL) for 1 hour. The solvent was removed and the residuewas dried and dissolved in water/acetonitrile, made acidic with TFA(pH=2), then purified on prep RPHPLC to give 2.2 g of yellow foam solidas the trifluoroacetic acid salt of the title compound. The ¹H NMR, MS,and HPLC were consistent with the desired compound. MS (CI) M+Hcalculated for C₂₀H₂₄N₃O₅S₂C2HF3O2: 550, found 550.

EXAMPLE 117 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-hydroxyphenylglycine)]phenyl]sulfonyl2H-thiopyran-4-carboxamide

Step A: To a solution of the title compound of Example 50 (MW 402, 5 g,1.0 equivalents) in N,N-dimethylacetamide (50 mL) was addedhydroxyphenylglycine (3 g, 2 equivalents), followed by cesium carbonate(10 g, 2.0 equivalents). The reaction was heated at 95 degrees Celsiusfor 5 hours, until HPLC indicated the reaction had finished. Thereaction mixture was filtered, the N,N-dimethylacetamide was removed invacuo. The solvent was removed, the residue was dried and dissolved inwater/acetonitrile, made acidic with trifluoroacetic acid (pH=2), thenpurified on prep RPHPLC to give 2.0 g of the crude methyl ester as a tansolid. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound.

Step B: The crude methyl ester from reaction Step A was stirred inaqueous HCl (50 mL) for 1 hour. The solvent was removed and the residuewas dried and dissolved in water/acetonitrile, made acidic withtrifluoroacetic acid (pH=2), then purified on prep RPHPLC to give 2.2 gof tan foam/solid as the trifluoroacetic acid salt of the titlecompound. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound. MS (CI) M+H calculated for C₂₀H₂₂N₂O₇S₂C₂HF₃O₂: 580, found580.

EXAMPLE 118 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-hydroxyphenylglycine)]phenyl]sulfonyl2H-thiopyran-4-carboxamide

Step A: A solution of the title compound of Example 115 (MW 518, 2.5 g,1.0 equivalents) in THF (25 mL)and N-Boc N-hydroxysuccinyl glycine (2.1g, 2 equivalents) containing N-methylmorpholine (2 mL) and4-dimethylaminopyridine (250 mg) was stirred for 12 hours. After RPHPLCindicated complete reaction at this time, the solvent was removed underreduced pressure to give an oil. Hydrochloric acid 10% aqueous solutionwas added with stirring for an additional 1-2 hours. The solution wasthen purified on prep RPHPLC to give 1.2 g of white foam/solid as thetrifluoroacetic acid salt. The ¹H NMR, MS, and HPLC were consistent withthe desired compound. The solid was dried under reduced pressure, thensuspended in ethyl ether followed by addition of 4N HCl/dioxane (20 mL).The HCl salt was filtered and washed with ethyl ether to give the titlecompound as a tan solid (1.1 g). The ¹H NMR, MS, and HPLC wereconsistent with the desired compound. MS (CI) M+H calculated forC₂₀H₂₃N₃O₅S₃C₂HF₃O₃ 595, found 595.

EXAMPLE 119 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-pyridinylthio)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide,monohydrochloride

Step A: To a solution of the title compound of Example 50 (MW 402, 5 g,1.0 equivalents) in N,N-dimethylacetamide (50 mL) were added4-thiopyridine (3 g, 2 equivalents), followed by cesium carbonate (10 g,2.0 equivalents). The reaction mixture was heated at 75 degrees Celsiusfor 5 hours, until HPLC indicated the reaction had finished. Thereaction mixture was filtered, and the N,N-dimethylacetamide was removedin vacuo. The residue was dried and dissolved in water/acetonitrile,made acidic with trifluoroacetic acid (pH=2), then purified on prepRPHPLC to give 2.0 g of the crude-S-pyridyl THP-protected thiopyrancompound as a brown solid. The ¹H NMR, MS, and HPLC were consistent withthe desired compound.

Step B: The -S-pyridyl THP-protected thiopyran compound from Step A wasstirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed andthe residue was dried and dissolved in water/acetonitrile, made acidicwith trifluoroacetic acid (pH=2), then purified on prep RPHPLC to give1.8 g of tan foam/glass as the trifluoroacetic acid salt of the titlecompound. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound. MS (CI) M+H calculated for C₁₇H₁₈N₂O₄S₃HCl: 447, found 447.

EXAMPLE 120 Preparation of4-[[4-[(4-aminophenyl)thio]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Step A: To a solution of the title compound of Example 55 (MW 387, 5 g,1.0 equivalents) in N,N-dimethylacetamide (50 mL) were added the4-aminothiophenol (3 g, 2 equivalents) followed by potassium carbonate(10 g, 2.0 equivalents). The reaction was heated at 60 degrees Celsiusfor 5 hours, until HPLC indicated the reaction had finished. Thereaction mixture was filtered, the DMA was removed in vacuo. The solventwas removed and the residue was dried and dissolved inwater/acetonitrile, made acidic with trifluoroacetic acid (pH=2), thenpurified on prep RPHPLC to give 2.0 g of the crude 4-amino-S-PhTHP-protected thiopyran as a brown solid. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound.

Step B: The 4-amino-S-Ph THP-protected thiopyran compound of Step A wasstirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed andthe residue was dried and dissolved in water/acetonitrile, made acidicwith trifluoroacetic acid (pH=2), then purified on prep RPHPLC to give1.4 g of tan foam/glass as the trifluoroacetic acid salt of the titlecompound. The ¹H NMR, MS, and HPLC were consistent with the desiredcompound. MS (CI) M+H calculated for C₁₈H₂N₂O₅S₂: 408, found 408.

EXAMPLE 121 Preparation oftetrahydro-N-hydroxy-4-[[4-[(2-methyl-5-benzothiazolyl)oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Step A: To a solution of the title compound of Example 55 (MW 387, 10 g,1.0 equivalents) in DMA (50 mL) were added hydroxymethyl benzothiazole(8 g, 1.5 equivalents) followed by cesium carbonate (20 g, 2.0equivalents). The reaction was heated at 90 degrees Celsius for 5 hours,until HPLC indicated the reaction had finished. The reaction mixture wascooled then filtered, the N,N-dimethylacetamide was discarded. Thefilter cake was placed in 10% aqueous HCl and stirred for 30 minutes toremove the cesium salts. The desired solid separated out of solution asa gum. This gum was dissolved in ethyl aceatate (100 mL) and was washedwith water and dried over sodium sulfate. The solvent was removed invacuo to give an oil that was dissolved in water/acetonitrile, madeacidic with trifluoroacetic acid (pH=2), then purified on prep RPHPLC togive the 2-methyl-5-benzothiazolyloxy compound. The ¹H NMR, MS, and HPLCwere consistent with the desired compound.

Step B: The 2-methyl-5-benzothiazolyloxy compound of Step A was stirredin aqueous HCl (20 mL)/acetonitrile (20 mL) for 1 hour. The solvent wasconcentrated and the solid that separated was filtered to give 6.5 g ofthe title compound. The ¹H NMR, MS, and HPLC were consistent with thedesired compound. MS (CI) M+H calculated for C₂₀H₂₀N₂O₆S₂: 448, found448.

EXAMPLE 122 Preparation of4-[[4-(4-chloro-3-fluorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboximide

Step A: To a solution of the title compound of Example 55 (MW 387, 10 g,1.0 equivalents) in N,N-dimethylacetamide (50 mL) were added4-chloro-3-flourophenol (7 g, 1.4 equivalents) followed by cesiumcarbonate (20 g, 2.0 equivalents). The reaction was heated at 90 degreesCelsius for 5 hours, until HPLC indicated the reaction had finished. Thereaction mixture was cooled then filtered, the DMA was discarded. Thefilter cake was placed in 10% aqueous HCl and stirred for 30 minutes toremove the cesium salts. The desired 4-chloro-3-fluorophenoxy compound(11 g) separated out of solution and was filtered. The ¹H NMR, MS, andHPLC were consistent with the desired compound.

Step B: The 4-chloro-3-fluorophenoxy compound (3.4 g) of Step A wasstirred in aqueous HCl (20 mL)/acetonitrile (20 mL) for 1 hour. Thesolvent was concentrated and the solid that separated was filtered togive 2.0 g of the title compound. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound. MS (CI) M+H calculated forC₁₈H₁₇ClFNO₆S: 429, found 429.

EXAMPLE 123 Preparation of4-[[4-[4-(4-acetyl-1-piperazinyl)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,trifluoroacetic acid salt

Step A: To a solution of the title compound of Example 55 (MW 387, 5 g,1.0 equivalents) in DMA (50 mL) were added1-acetyl-4-(4-hydroxyphenyl)piperazine (3 g, 2 equivalents) followed bycesium carbonate (10 g, 2.0 equivalents). The reaction was heated at 90degrees Celsius for 5 hours, until HPLC indicated the reaction hadfinished. The reaction mixture was filtered, the DMA was removed invacuo. The residue was dissolved in water/acetonitrile, made acidic withTFA (pH=2), then purified on prep RPHPLC to give 3.1 g of the crude4-acetyl-1-piperazinylphenoxy compound as a brown solid. The ¹H NMR, MS,and HPLC were consistent with the desired compound.

Step B: The 4-acetyl-1-piperazinylphenoxy compound from reaction Step Awas stirred in aqueous HCl (50 mL) for 1 hour. The solvent was removedand the residue was dried and dissolved in water/acetonitrile, madeacidic with TFA (pH=2), then purified on prep RPHPLC to give 2.0 g oftan foam as the trifluoroacetic acid salt of the title compound. The ¹HNMR, MS, and HPLC were consistent with the desired compound. MS (CI) M+Hcalculated for C₂₄H₂₉N₃O₇SC₂HF₃O₂: 617, found 617.

EXAMPLE 124 Preparation ofN,N-dimethyl-5-[4-[[tetrahydro-4-[(hydroxyamino)carbonyl]-2H-pyran-4-yl]sulfonyl]-phenoxy]-1H-indole-2-carboxamide,trifluoroacetic acid salt

Step A: To a solution of the title compound of Example 55 (MW 387, 5 g,1.0 equivalents) in DMA (50 mL) were added the 5-hydroxy-2-indoledimethylcarboxylate (3 g, 2 equivalents) followed by Cs₂CO₃ (10 g, 2.0equivalents). The reaction was heated at 90 degrees Celsius for 5 hours,until HPLC indicated the reaction had finished. The reaction mixture wasfiltered, the DMA was removed in vacuo. The residue was dissolved inwater/acetonitrile, made acidic with TFA (pH=2), then purified on prepRPHPLC to give 2.1 g of the crude THP-protected pyran hydroxamatecompound as a brown solid. The ¹H NMR, MS, and HPLC were consistent withthe desired compound.

Step B: The THP-protected pyran hydroxamate compound from Step A wasstirred in aqueous HCl (50 mL) for 1 hour. The solvent was removed andthe residue was dried and dissolved in water/acetonitrile, made acidicwith TFA (pH=2), then purified on prep RPHPLC to give 1.5 g of tan solidas the trifluoroacetic acid salt of the title compound. The ¹H NMR, MS,and HPLC were consistent with the desired compound. MS (CI) M+Hcalculated for C₂₃H₂₅N₃O₇S: 487, found 487.

EXAMPLE 125 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Step A: To a solution of the title compound of Example 55 (MW 387, 5 g,1.0 equivalents) in DMA (50 mL) was added the 4-isopropylphenol (3 g, 2equivalents), followed by cesium carbonate (10 g, 2.0 equivalents). Thereaction mixture was heated at 90 degrees Celsius for 8 hours, untilHPLC indicated the reaction had finished. The reaction mixture wasfiltered, the DMA portion was discarded. The filter cake was placed in10% aqueous HCl and stirred for 30 minutes to remove the cesium salts.The solid (3.5 g) isopropylphenoxyphenyl THP-protected hydroxamateseparated and was filtered. The ¹H NMR, MS, and HPLC were consistentwith the desired compound.

Step B: Into a stirred solution of aqueous HCl (20 mL) and acetonitrile(20 mL) was added the crude isopropyl-phenoxyphenyl THP-protectedhydroxamate from Step A and the resulting mixture was stirred for 1-2hours. The solvent was concentrated via a stream of nitrogen over thesurface of the solution. The solid was filtered and dried to give 2.2 gof the title compound as a tan solid. The ¹H NMR, MS, and HPLC wereconsistent with the desired compound. MS (CI) M+H calculated forC₂₁H₂₅NO₆S: 419, found 419.

EXAMPLE 126 Preparation of Resin II

Step 1: Attachment of Compound of Example 55, Part D, to Resin I

A 500 mL round-bottomed flask was charged with of resin I [Floyd et al.,Tetrahedron Lett. 1996, 37, 8045-8048](8.08 g, 9.7 mmol) and1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was added, andthe resin slurry slowly stirred. A separate solution of the compound ofPart D, Example 55 (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35mL) was added to the slurry followed by addition ofbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(10.1 g, 19.4 mmol) in one portion. Once the hexafluorophosphate salthad dissolved, 4-methylmorpholine (4.26 mL, 39 mmol) was added dropwise.The reaction slurry was stirred at room temperature for 24 hours, thenthe resin was collected in a sintered-disc funnel and washed withN,N-dimethylformamide, methanol, methylene chloride and diethyl ether(3×30 mL each solvent). The resin was dried in vacuo to yield 10.99 gpolymer-bound hydroxymate as a tan polymeric solid. Theoretical loadingon polymer was 0.91 mmol/g. FTIR microscopy showed bands at 1693 and3326 cm⁻¹ indicative of the hydroxamate carbonyl and nitrogen-hydrogenstretches, respectively.

Step 2: Preparation of Resin III: Reaction of Resin II with Nucleophiles

Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial, and a0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) wasadded to the vessel. In the case of phenol and thiophenol nucleophiles,cesium carbonate (148 mg, 0.46 mmol) was added, and in the case ofsubstituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46mmol) was added. The vial was capped and heated to 70 to 155 degreesCelsius for 24-48 hours, then cooled to room temperature. The resin wasdrained and washed with 1-methyl-2-pyrrolidinone,1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water,methanol, and methylene chloride (3×3 mL each solvent).

Step 3: Cleavage of Hydroxamic Acids from the Polymer-support

Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1mL) for 1 hour at room temperature. During that time, the resin became adeep red color. The resin was then drained and washed withtrifluoroacetic acid/water (19:1) and methylene chloride (2×1 mL eachsolvent), collecting the combined filtrates in a tared vial. Thevolatiles were removed in vacuo, then a toluene/methylene chloridemixture (2 mL each) was added to the residue. The mixture was againconcentrated in vacuo. The product was characterized by electrospraymass spectroscopy.

The following hydroxamic acids were synthesized from resin II using theconditions of Step 2 with the indicated nucleophile, followed by releasefrom the polymer using Step 3 reaction conditions.

Example MS (ES) Number R Nucleophile m/z 126-1 

4′-hydroxy-2′- methylacetophenone 451 (M + NH₄) 126-2 

5,6,7,8-tetrahydro- 2-naphthol 455 (M + NH₄) 126-3 

3,4-dichlorophenol 462 (M + NH₄) 126-4 

4-hydroxyphenethyl alcohol 439 (M + NH₄) 126-5 

4-hydroxy diphenylmethane 485 (M + NH₄) 126-6 

4-phenylphenol 471 (M + NH₄) 126-7 

4-(methylthio)phenol 441 (M + NH₄) 126-8 

3-methoxyphenol 425 (M + NH₄) 126-9 

4-chlorophenol 429 (M + NH₄) 126-10

4-bromophenol 590 (M + Cs) 126-11

4-(imidazol-1-yl)- phenol 444 (M + H) 126-12

3-hydroxyphenethyl alcohol 439 (M + NH₄) 126-13

3-(4-hydroxy- phenyl)-1-phenol 453 (M + NH₄) 126-14

4-bromo-3- methylphenol 487 (M + NH₄) 126-15

3-hydroxybenzyl alcohol 425 (M + NH₄) 126-16

4-methoxyphenol 425 (M + NH₄) 126-17

4-chloro-3- methylphenol 558 (M + Cs) 126-18

2-naphthol 560 (M + Cs) 126-19

p-cresol 409 (M + NH₄) 126-20

4-hydroxybenzyl alcohol 408 (M + H) 126-21

1-naphthol 445 (M + NH₄) 126-22

3-hydroxypyridine 379 (M + H) 126-23

8-hydroxyjulolidine 473 (M + H) 126-24

2,6-quinolinediol 445 (M + H) 126-25

5-hydroxy-2- methylpyridine 393 (M + H) 126-26

2,3-dihydroxy- pyridine 412 (M + H) 126-27

4-hydroxyphenyl acetic acid 453 (M + NH₄) 126-28

4-amino-m-cresol 407 (M + H) 126-29

8-quinolinol 429 (M + H) 126-30

4-cyclopentylphenol 463 (M + NH₄) 126-31

3,4-dimethyl- thiophenol 439 (M + NH₄) 126-32

m-thiocresol 425 (M + NH₄) 126-33

3-methoxythiophenol 441 (M + NH₄) 126-34

4-methoxythiophenol 441 (M + NH₄) 126-35

4-fluorothiophenol 429 (M + NH₄) 126-36

3-chlorothiophenol 445 (M + NH₄) 126-37

4-chlorothiophenol 445 (M + NH₄) 126-38

4-aminothiophenol 426 (M + NH₄) 126-39

2-naphthalenethiol 461 (M + NH₄) 126-40

piperidine 126-41

4-benzyl-4- hydroxypiperidine 475 (M + H) 126-42

nipecotamide 468 (M + H) 126-43

3-hydroxypiperidine 385 (M + H) 126-44

4-(1-pyrrolidinyl)- piperidine 438 (M + H) 126-45

ethyl nipecotate 441 (M + H) 126-46

3-piperidinyl- methanol 512 (M + TFA) 126-47

4-benzylpiperidine 459 (M + H) 126-48

4-methylpiperidine 383 (M + H) 126-49

3-methylpiperidine 383 (M + H) 126-50

4-hydroxy-4- phenylpiperidine 461 (M + H) 126-51

ethyl isonipecotate 441 (M + H) 126-52

1,4-dioxa-8- azaspiro(4,5)decane 427 (M + H) 126-53

isonipecotamide 412 (M + H) 126-54

nipecotamide 412 (M + H) 126-55

4-piperidino- piperidine 452 (M + H) 126-56

morpholine 388 (M + NH₄) 126-57

4-phenylpiperidine 445 (M + H) 126-58

3,5-dimethyl- piperidine 414 (M + NH₄) 126-59

4-(4-bromophenyl)-4- piperidinol 539 (M + H) 126-60

1-methylpiperazine 384 (M + H) 126-61

4-piperazino- acetophenone 488 (M + H) 126-62

1-benzylpiperazine 460 (M + H) 126-63

N-(α,α,α-trifluoro-m- tolyl)piperazine 514 (M + H) 126-64

1-(2-pyridyl)- piperazine 447 (M + H) 126-65

1-(4-fluorophenyl)- piperazine 464 (M + H) 126-66

1-piperonyl- piperazine 504 (M + H) 126-67

1-(4-nitrophenyl)- piperazine 491 (M + H) 126-68

1-hydroxyethyl- ethoxypiperazine 458 (M + H) 126-69

1-acetylpiperazine 412 (M + H) 126-70

1-ethylpiperazine 398 (M + H) 126-71

1-(2-fluorophenyl)- piperazine 464 (M + H) 126-72

benzyl-1-piperazine carboxylate 504 (M + H) 126

ethyl-N-piperazine carboxylate 442 (M + H) 127

N-(2-hydroxyethyl)- piperazine 414 (M + H) 128

1-(2-methoxy- phenyl)piperazine 476 (M + H)

EXAMPLE XX Large Scale Preparation of Resin IIIa

Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-neckedround bottom flask fitted with a temperature probe, an overhead stirringpaddle, and a nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidinone (35 mL)was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5mmol). The resin slurry was stirred slowly with the overhead stirrer,and the mixture was heated to 80 degrees Celsius with a heating mantlefor 65 hours. The flask was thereafter cooled to room temperature.

The resin was collected in a sintered-disk glass funnel and washed withN,N-dimethylformamide, methanol and methylene chloride (3×30 mL eachsolvent). The resin was dried in vacuo to provide 5.86 g of resin IIIaas off-white resin beads. The theoretical loading of the polymer was0.81 mmol/g. TFA cleavage performed on 50 mg of resin IIIa as describedin step 3 yielded 10.4 mg of off-white solid spectroscopicallyindistinguishable from the reaction product using ethyl isonipecotate ofExample 211.

EXAMPLE YY Large Scale Preparation of Resin IIIb:

Preparation of resin IIIb followed the procedure described forpreparation of resin IIIa, except ethyl nipecotate was substituted forethyl isonipecotate. The yield after drying in vacuo was 5.77 g of resinIIIb as pale yellow resin beads. The theoretical loading of the polymerwas 0.81 mmol/g. TFA cleavage performed on 50 mg of resin IIIb asdescribed in step 3 yielded 14.7 mg of off-white solid spectroscopicallyindistinguishable from the reaction product using ethyl nipecotate ofExample 212.

Step 4: Hydrolysis of Polymer-bound Ester: Preparation of Resin IVa

Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked roundbottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane wasadded to the flask, and the resin slurry was stirred for 15 minutes.Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixturewas stirred for 44 hours. The resin was thereafter collected in asintered-disk glass funnel and washed with dioxane/water (9:1), water,10% acetic acid/water, methanol and methylene chloride (3×30 mL eachsolvent). The resin was dried in vacuo to yield 5.64 g of resin IVa asoff-white polymer beads. FTIR microscopy showed bands at 1732 and 1704cm⁻¹ and a broad band from 2500-3500 cm⁻¹. The theoretical loading ofthe polymer-bound acid was 0.84 mmol/g.

Preparation of Resin IVb

Using the procedure described in Step 4, resin IIIb (5.71 g, 4.5 mmol)was converted into 5.61 g of resin IVb. FTIR microscopy showed bands at1731 and 1705 cm⁻¹ and a broad band from 2500-3500 cm⁻¹. The theoreticalloading of the polymer-bound acid was 0.84 mmol/g.

Step 5: Amide Bond Formation: Preparation of Resin V

Into a fritted reaction vessel was weighed either resin IVa or resin IVb(50 mg, 0.042 mmol), and the vessel was capped under nitrogen. A 0.5 Msolution of hydroxybenzotriazole in 1-methyl-2-pyrrolidinone (0.3 mL,0.15 mmol) was added followed by a 0.5 M solution ofdiisopropylcarbodiimide in 1-methyl-2-pyrrolidinone (0.3 mL, 0.15 mmol).The resin was stirred using a tabletop stirring plate for 15 minutes,then a 0.7 M solution of the amine in 1-methyl-2-pyrrolidinone (0.3 mL,0.21 mmol) was added. The reaction mixture was stirred for 6 hours, thenthe resin was drained and washed with 1-methyl-2-pyrrolidinone (3×1 mL).The reaction was repeated using the same amounts of reagents describedabove. The reaction mixture was stirred for 16 hours, then the resin wasdrained and washed with 1-methyl-2-pyrrolidinone, methanol and methylenechloride (3×1 mL each solvent).

The following hydroxamic acids were synthesized using the indicatedpolymer-bound acid and the indicated amine in Step 5 reaction conditionsfollowed by release from the polymer using Step 3 reaction conditions.

Example MS (ES) Number Resin Amine R Position m/z 129 IVa —

4 130 IVa methylamine

4 131 IVa morpholine

4 482 (M + H) 132 IVa ethanolamine

4 456 (M + H) 133 IVa 1,3-diamino- propane

4 469 (M + H) 134 IVa ethylamine

4 440 (M + H) 135 IVa glycine t- butyl ester HCl

4 470 (M + H) 136 IVa L-histidine methyl ester HCl

4 564 (M + H) 137 IVa

4 428 (M + H) 138 IVb —

3 139 IVb methylamine

3 426 (M + H) 140 IVb morpholine

3 482 (M + H) 141 IVb ethanolamine

3 456 M + H) 142 IVb 1,3-diamino- propane

3 469 (M + H) 143 IVb ethylamine

3 440 (M + H) 144 IVb glycine t- butyl ester HCl

3 470 (M + H) 145 IVb L-histidine methyl ester HCl

3 564 (M + H) 146 IVb

3 428 (M + H) 147 IVa dimethylamine

4 440 (M + H) 148 IVa diethylamine

4 468 (M + H) 149 IVa piperidine

4 480 (M + H) 150 IVa 1-methyl- piperazine

4 495 (M + H) 151 IVa N-Boc- piperazine

4 481 (M + H) 152 IVa ethyl isonipecotate

4 552 (M + H) 153 IVa ethyl nipecotate

4 552 (M + H) 154 IVa ethyl pipecolate

4 552 (M + H) 155 IVb dimethylamine

3 440 (M + H) 156 IVb piperidine

3 480 (M + H) 157 IVb 1-methyl- piperazine

3 495 (M + H) 158 IVb N-Boc- piperazine

3 481 (M + H) 159 IVb ethyl isonipecotate

3 552 (M + H) 160 IVb ethyl nipecotate

3 552 (M + H) 161 IVb ethyl pipecolate

3 552 (M + H) 162 IVb hexamethylene- imine

3 494 (M + H) 163 IVb 1,3,3- trimethyl-6- azabicyclo [3.2.1]-octane

3 548 (M + H) 164 IVa 1,3,3- trimethyl-6- azabicyclo [3.2.1]-octane

4 548 (M + H) 165 IVa hexamethylene- imine

4 494 (M + H) 166 IVb 3-pyrrolidinol

3 482 (M + H) 167 IVb (3S)-(-)-3- (dimethyl amino)- pyrrolidine

3 509 (M + H) 168 IVb (3S)-(-)-3- (t-butoxy- carbonylamino)- pyrrolidine

3 481 (M + H) 169 IVb cis-2,6- dimethyl- morpholine

3 510 (M + H) 170 IVb decahydro- quinoline

3 534 (M + H) 171 IVb 4-(1- pyrrolidinyl)- piperidine

3 549 (M + H) 172 IVb pyrrolidine

3 466 (M + H) 173 IVa 3-pyrrolidinol

4 482 (M + H) 174 IVa (3S)-(-)-3- (dimethyl amino)- pyrrolidine

4 509 (M + H) 175 IVa (3S)-(-)-3- (t-butoxy- carbonylamino)- pyrrolidine

4 481 (M + H) 176 IVa cis-2,6- dimethyl- morpholine

4 510 (M + H) 177 IVa decahydro- quinoline

4 534 (M + H) 178 IVa 4-(1- pyrrolidinyl)- piperidine

4 549 (M + H) 179 IVa pyrrolidine

4 466 (M + H) 180 IVa 2,2,2-tri- fluoroethyl- amine

4 494 (M + H) 181 IVa butylamine

4 468 (M + H) 182 IVa diallylamine

4 492 (M + H) 183 IVa 3,3′- iminobis(N,N- dimethylpropyl- amine)

4 582 (M + H) 184 IVa iso- propylamine

4 454 (M + H) 185 IVa 4-amino- morpholine

4 497 (M + H) 186 IVa 3- (aminomethyl)- pyridine

4 503 (M + H) 187 IVa cyclohexyl- amine

4 494 (M + H) 188 IVa 1-aminoindane

4 528 (M + H) 189 IVa 2-thiophene- methylamine

4 508 (M + H) 190 IVa 4-methyl- piperidine

4 494 (M + H) 191 IVa 4-benzyl- piperidine

4 570 (M + H) 192 IVa 4-phenyl- piperidine

4 556 (M + H) 193 IVa 4-benzyl-4- hydroxy- piperidine

4 586 (M + H) 194 IVa cycloheptyl- amine

4 508 (M + H) 195 IVa 4-aminomethyl- pyridine

4 503 (M + H) 196 IVa 2-amino- methyl- pyridine

4 503 (M + H) 197 IVa 4-fluoro- benzylamine

4 520 (M + H) 198 IVa dibenzylamine

4 592 (M + H) 199 IVa 1,2,3,4- tetrahydro- isoquinoline

4 528 (M + H)

Large Scale Preparation of Resin IIIc

Resin II (3.01 g, 2.74 mmol) was weighed into an oven-dried three-neckedround bottomed flask fitted with an overhead stirring paddle, atemperature probe and an nitrogen inlet. 1-Methyl-2-pyrrolidinone (25mL) was added followed by piperazine (2.36 g, 27.4 mmol) and cesiumcarbonate (8.93 g, 27.4 mmol). Additional 1-methyl-2-pyrrolidinone (10mL) was added, and the reaction mixture was heated to 100 degreesCelsius and stirred 18 hours. The flask was cooled to room temperature,and the resin was collected in a sintered-disc funnel and washed withN,N-diethylformamide/water (1:1), water, 10% acetic acid/water,methanol, and methylene chloride (3×30 mL each solvent). The yield afterdrying in vacuo was 3.14 g of resin IIIb as pale yellow resin beads. Thetheoretical loading of the polymer was 0.86 mmol/g. TFA cleavageperformed on 50 mg of resin IIIb as described in Step 3 yielded 21 mg ofoff-white solid spectroscopically indistinguishable from the compound ofExample 209.

Step 6: Amide Bond Formation with resin IIIc: Preparation of Resin VI

Into a fritted reaction vessel was placed the carboxylic acid (0.215mmol) and 1-hydroxybenzotriazole (44 mg, 0.326 mmol). The vessel wascapped under nitrogen, and 1-methyl-2-pyrrolidinone was added followedby diisopropylcarbodiimide (0.034 mL, 0.215 mmol). The solution wasagitated on a tabletop shaker for 15 minutes, then resin IIIc (50 mg,0.043 mmol) was added in one portion. The reaction mixture was shakenfor 16 hours, then the resin was drained and washed with1-methyl-2-pyrrolidinone, methanol and methylene chloride (3×1 mL eachsolvent). In the case of N-9-fluorenyl-methoxycarbonyl-protected aminoacids, the resin was further treated with apiperidine/N,N-dimethylformamide solution (1:4, 1 mL) for 30 minutes.The resin was drained and washed with N,N-dimethylformamide, methanoland methylene chloride (3×1 mL each solvent).

The following hydroxamic acids were synthesized from resin IIIc usingStep 6 with the indicated carboxylic acid, followed by release from thepolymer using Step 3 reaction conditions.

Exam- ple Carboxylic MS (ES) Number Acid R m/z 200 cyclo-hexanecarboxylic acid

502 (M + Na) 201 1,2,3,4-tetra- hydronaphthylene- 2-carboxylic acid

545 (M + NH₄) 202 cycloheptane- carboxylic acid

511 (M + NH₄) 203 N-9- fluorenylmethoxy- carbonyl-L- proline

467 (M + H) 204 N-9- fluorenylmethoxy- carbonyl-L-valine

469 (M + H)Step 7: Preparation of Resin VII

Resin IIIc (1.0 g, 0.86 mmol) was weighed into an oven-dried 100 mLround-bottomed flask and a magnetic stirring bar and septum with anitrogen needle were added. Methylene chloride (10 mL) was added, andthe resin slurry was slowly stirred. p-Nitrophenylchloro-formate (0.867g, 4.3 mmol) was added in one portion, followed by dropwise addition ofdiisopropylethylamine (0.75 mL, 4.3 mmol). A slight warming was notedwith the addition. The reaction was stirred at room temperature for 18hours, then the resin was collected in a sintered-disc glass funnel andwashed with methylene chloride, methanol and methylene chloride (3×10 mLeach solvent).

The polymer-bound product was dried in vacuo yielding 1.25 g of resinVII as brown resin beads. FTIR microscopy showed bands at 1798, 1733,1696 and 1210 cm⁻¹. Theoretical loading of the polymer was 0.75 mmol/g.

Step 8: Reaction of Resin VII with Amines Preparation of Resin VIII

An 8 mL vial was charged with resin VII (50 mg, 0.038 mmol) and a smallmagnetic stirring bar, and a 0.5 M solution of the amine in1-methyl-2-pyrrolidinone (1 mL) was added. The vial was capped andheated to 50 degrees Celsius. The resin slurry was gently stirred for 15hours, then the vial was cooled to room temperature. The resin wascollected in a fritted reaction vessel and washed with1-methyl-2-pyrrolidinone, methanol and methylene chloride (3×1 mL eachsolvent).

The following hydroxamic acids were synthesized from resin VII usingStep 8 reaction conditions with the indicated amine, followed by releasefrom the polymer using Step 3 reaction conditions.

Example Carboxylic MS (ES) Number Acid R m/z 205 —

535 (M + H) 206 piperidine

481 (M + H) 207 morpholine

501 (M + Na) 208 dimethylamine

441 (M + H) 209 piperazine

482 (M + H) 210 1-methyl- piperazine

496 (M + H) 211 ethyl isonipecotate

553 (M + H) 212 ethyl nipecotate

553 (M + H)

EXAMPLE xxx Preparation of4-[(4-bromophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic Acid

Part A: Preparation of

A 60% sodium hydride oil dispersion (4.0 g, 0.1 mole) was weighed intoan oven-dried 3-necked 500 mL round-bottomed flask in a nitrogen glovebag and the flask was fitted with an nitrogen inlet, a temperatureprobe, an overhead stirring paddle and rubber septa. Anhydroustetrahydrofuran (200 mL) was added to the flask, which was then cooledin an ice bath. 4-Bromothiophenol (18.91 g, 0.1 mole) was addeddropwise, maintaining a temperature less than 7 degrees Celsius.Vigorous gas evolution was noted throughout addition. After completeaddition, the mixture was stirred for 10 minutes with cooling. Then,methyl bromoacetate (9.5 mL, 0.1 mole) was added dropwise, maintaining atemperature less than 7 degrees Celsius. The reaction was stirred for 10minutes with cooling, then the ice bath was removed and the mixturestirred an additional 30 minutes. The reaction was quenched by theaddition of 5 mL water, then solvent was removed on rotary evaporator.The residual oil was partitioned between ethyl acetate (200 mL) andwater (200 mL). The organic layer was washed with 5% hydrogenchoride/water (1×200 mL), saturated sodium bicarbonate (1×200 mL) andbrine (1×200 mL). The organic phase was dried over magnesium sulfate andconcentrated to give 24.53 g of the product as a yellow oil (94%). ¹HNMR was consistent with the desired structure. The mass spectrum showedan m/z 260 (M+H).

Part B: Preparation of

The compound of part A, above, (24.5 g, 0.094 mole) was weighed into a1.0 L round-bottomed flask fitted with an overhead stirring paddle andtemperature probe, then 550 mL of methanol were added, followed by 55 mLof water, causing the solution to become slightly turbid. The flask wasimmersed in an ice bath, and once the temperature fell below 5 degreesCelsius, Oxone® (144.5 g, 0.235 mole) was added portionwise over 5minutes. A slight increase in temperature to 8 degrees Celsius wasnoted. The reaction was stirred with cooling for 10 minutes, then theice bath was removed. After 4 hours, reversed-phase high pressure liquidchromatography showed a single component at 13.6 minutes. The reactionmixture was filtered, and the solid washed exhaustively with methanol.The combined filtrates were concentrated on a rotary evaporator, and theresidual material partitioned between ethyl acetate (300 mL) and water(200 mL). The organic layer was washed with water (3×200 mL), saturatedsodium bicarbonate (1×200 mL) and brine (1×200 mL), then the organicphase was dried over magnesium sulfate and concentrated to give 25 g ofthe product as a tan solid. Trituration with hexane provided 24.3 g ofpure sulfone as an off-white solid (88%). ¹H NMR was consistent with thedesired structure. The mass spectrum showed an m/z 293 (M+H).

Part C: Preparation of

A 60% sodium hydride oil dispersion (5.76 g, 0.144 mole) was weighedinto an oven-dried 3-necked 1.0 L round-bottomed flask in a nitrogenglove bag, and then the flask was fitted with an nitrogen inlet, atemperature probe, an overhead stirring paddle and rubber septa.Anhydrous N,N-dimethylformamide (250 mL) was added to the flask,mechanical stirring was initiated, and the mixture heated to 50 degreesCelsius. A solution of the compound of part B, above, (17.59 g, 0.06mole) and dibromodiethyl ether (14.5 g, 0.06 mole) in 40 mL ofN,N-dimethylformamide was added dropwise to the sodium hydride slurry,maintaining a temperature between 50-55 degrees Celsius and a steadyevolution of hydrogen. After complete addition, the temperature of thereaction mixture was increased to 65 degrees Celsius, and the mixturewas stirred for 2 hours. The flask was then cooled to room temperature,and the flask was immersed in an ice bath. When the temperature fellbelow 20 degrees Celsius, 0.5 L ice water was added.

The mixture was transferred to a 4.0 L separatory funnel, an additional1.0 L of water was added, and the mixture was extracted with ethylacetate (3×200 mL) The combined organic layers were washed with 5%hydrogen chloride/water (1×200 mL), saturated sodium carbonate (1×200mL), and brine (1×200 mL), dried over magnesium sulfate, andconcentrated in vacuo to give 18.2 g of crude product as a yellowsemi-solid. Recrystallization from ethyl acetate/hexane gave 6.53 g ofpure product as tan crystals (30%). ¹H NMR was consistent with thedesired structure. The mass spectrum showed an m/z 363 (M+H).

Part D: Preparation of the Title Compound

A solution of the compound of part C, above, (4.57 g, 12.6 mmol) in 50mL of dry tetrahydrofuran in an oven-dried 100 mL round-bottomed flaskwas stirred at room temperature under nitrogen, and 4.84 g of potassiumtrimethylsilanolate (37.7 mmol) were added in one portion. The mixturewas stirred for two hours, then 10 mL of water were added dropwise. Thevolatiles were removed in vacuo, and the residue partitioned between 100mL ethyl ether and 100 mL water. The aqueous layer was acidified to a pHvalue of less than 2 using concentrated hydrogen chloride, causing awhite precipitate. This mixture was extracted with ethyl acetate (3×75mL), and the combined ethyl acetate layers were dried over magnesiumsulfate and concentrated in vacuo to give 4.15 g of pure product as awhite solid (94%). ¹H NMR (CDCl/CD₃OD) 2.10 (m, 4H), 3.28 (m, 2H), 3.90(m, 2H), 7.60 (m, 4H). The mass spectrum showed an m/z 349 (M+H).

Step 9: Attachment to Resin I: Preparation of Resin IX

Following the procedure outlined in Step 1 before, 3.13 g of the titlecompound of the above preparation was reacted with 3.73 g of resin I togive 5.19 g of polymer-bound hydroxymate as a tan polymeric solid.Theoretical loading on polymer was 0.86 mmol/g. FTIR microscopy showedbands at 1693 and 3332 cm⁻¹ indicative of the hydroxamate carbonyl andnitrogen-hydrogen stretches, respectively.

Step 10: Palladium Catalyzed Reaction of Resin IX with Boronic Acids:Preparation of Resin VII

Into an 8 mL glass solid phase reaction vessel was weighed resin IX (50mg, 0.043 mmol). The resin was washed with dry dimethoxyethane (2×3 mL).A 0.017 M solution of the palladium tetrakistriphenyl phosphine (0.6 mL,0.01 mmol) was added to the vessel followed by a 0.6 M solution of theboronic acid in 1:1 dimethoxyethane/ethanol (0.6 mL, 0.36 mmol) and a 2Msolution of potassium hydroxide in water (0.4 mL, 0.8 mmol). The vesselwas maintained under a positive pressure of argon and heated at 90degrees Celsius 16 hours. The vessel was cooled to room temperature,then the resin was drained and washed with 1-methyl-2-pyrrolidinone,1-methyl-2-pyrrolidinone/water (1:1), water, acetic acid/water (1:9),methanol, and methylene chloride (3×3 mL each solvent).

The following hydroxamic acids were synthesized from resin IX using Step10 reaction conditions with the indicated boronic acid, followed bycleavage from the polymer using Step 3 reaction conditions.

Example MS (ES) Number Boronic Acid R m/z 213 phenylboronic acid

362 (M + H) 214 3-nitrophenyl- boronic acid

424 (M + NH₄) 215 thiophene-3- boronic acid

368 (M + H) 216 4-chlorobenzene boronic acid

413 (M + NH₄) 217 4-methyl- benzeneboronic acid

414 (M + K) 218 4-(2- pyrrolidinyl- ethoxy)- benzeneboronic acid

476 (M + NH₄) 219 3-(tri- fluoromethyl)- benzeneboronic acid

430 (M + H) 220 4-fluoro- benzeneboronic acid

418 (M + K) 221 4-(tri- fluoromethyl)- benzeneboronic acid

447 (M + NH₄) 222 4-fluoro-3- methylbenzene- boronic acid

411 (M + NH₄) 223 3,4-dimethyl- benzeneboronic acid

407 (M + NH₄) 224 1-naphthylene- boronic acid

412 (M + H) 225 2-methyl- benzeneboronic acid

376 (M + H) 226 4-t-butyl- benzeneboronic acid

418 (M + H) 227 2-naphthylene- boronic acid

412 (M + H) 228 3-formyl- benzeneboronic acid

390 (M + H) 229 benzofuran-2- boronic acid

419 (M + NH₄) 230 2-formyl- benzeneboronic acid

390 (M + H) 231 4-formyl- benzeneboronic acid

390 (M + H) 232 3-amino- benzeneboronic acid

377 (M + H)

EXAMPLE 233 Preparation of Monomethanesulfonate salts:N-hydroxy-4-[[4-(phenylthio)phenyl]-sulfonyl]-1-(2-propynyl)-4-piperidine-carboxamide,monomethanesulfonate

First Preparation

Part A: A solution of the compound of Example 9, Part J (2.1 g, 4.5mmol) in warm H₂O (200 mL) was admixed with NaHCO₃ at ambienttemperature. After stirring for 20 minutes, the resulting white solidwas isolated by filtration, washed with water and dried at 37 degreeCelsius in a vacuum oven to afford the free base of the title compoundas a white solid (1.7 g, 86%); Anal. calcd for C₂₁H₂₂N₂O₄S₂.0.3% H₂O: C,57.86; H, 5.23; N, 6.43; S, 14.71. Found: C, 57.84; H, 4.96; N, 6.39; S,14.89.

Part B: Methanesulfonic acid (0.28 mL, 4.1 mmol) was added to a solutionof the free base of part A (1.6 g, 3.7 mmol) in methanol (10 mL) atambient temperature. After 3 hours, the resulting solid was isolated byfiltration, washed with methanol, and dried at ambient temperature in avacuum oven to afford the monomethanesulfonate titled compound as awhite solid (1.6 g, 81%): Anal. calcd for C₂₁H₂₂N₂O₄S₂.CH₄O₃: C, 48.51;H, 5.18; N, 5.14; S, 17.66. Found: C, 48.88; H, 5.15; N, 5.23; S, 17.81.

Second Preparation Methanesulfonic acid (0.91 mL, 14 mmol) was added toa solution of the protected hydroxamate of Example 9, Part I (6.0 g, 12mmol) in methanol (37 mL) under a nitrogen atmosphere. After 1 hour, theprecipitate was isolated by filtration, washed with methanol, and driedat 40 degrees Celsius in a vacuum oven for 1 day to afford themonomethanesulfonate title compound as a white solid (5.5 g, 89%)identical to the material from Example 233, First Preparation.

Methanesulfonate salts of the other cyclic amine compounds disclosedherein can be similarly prepared using the methods of the above twopreparations.

EXAMPLES 234-280

The compounds of Example 234-280 were prepared as described for thecompounds of Example 129-199.

Example MS (ES) Number Resin Amine R Position m/z 234 IVb N-methylhomopiperazine

4 509 (M + H) 235 IVb 6,7-dimethoxy- 1,2,3,4- tetrahydro- isoquinolineHCl

4 588 (M + H) 236 IVb tetrahydro- pyridine

4 478 (M + H) 237 IVb R-3-hydroxy- piperidine HCl

4 496 (M + H) 238 IVb phenyl- piperazine

4 557 (M + H) 239 IVb benzyl- piperazine

4 571 (M + H) 240 IVa methyl homopiperazine

3 509 (M + H) 241 IVa 6,7-dimethoxy- 1,2,3,4- tetrahydro- isoquinolineHCl

3 588 (M + H) 242 IVa tetrahydro- pyridine

3 478 (M + H) 243 IVa R-3-hydroxy- piperidine HCl

3 496 (M + H) 244 IVa phenyl- piperazine

3 557 (M + H) 245 IVa benzyl- piperazine

3 571 (M + H) 246 IVb hydroxyethyl- piperazine

4 525 (M + H) 247 IVb 1-(2,3-xylyl)- piperazine HCl

4 585 (M + H) 247 IVb 1-(4-methoxy- phenyl)- piperazine 2HCl

4 587 (M + H) 249 IVb 1-(3- chlorophenyl)- piperazine HCl

4 591 (M + H) 250 IVb 1-(m-tolyl)- piperazine 2HCl

4 571 (M + H) 251 IVb 1-(2,5-dimethyl- phenyl)piperazine

4 585 (M + H) 252 IVb 1-(p-toyl)- piperazine 2HCl

4 571 (M + H) 253 IVb 1-(3-methoxy- phenyl)- piperazine 2HCl

4 587 (M + H) 254 IVb 1-(3,4-dichloro- phenyl)piperazine

4 625 (M + H) 255 IVb 1-(2-methoxy)- piperazine HCl

4 587 (M + H) 256 IVb nipecotamide

4 523 (M + H) 257 IVb isonipecotamide

4 523 (M + H) 258 IVb 1-(2-(2-hydroxy- ethoxyethyl)- piperazine

4 569 (M + H) 259 IVb 1-ethyl- piperazine

4 509 (M + H) 260 IVb 1-(2- chlorophenyl)- piperazine HCl

4 591 (M + H) 261 IVb 1-(4-methoxy- phenyl)-2-methyl- piperazine

4 601 (M + H) 262 IVb 2-methyl- piperidine

4 494 (M + H) 263 IVb 3,5-dimethyl- piperidine

4 508 (M + H) 264 IVb N-(2-piperidyl- methyl)- diethylamine

4 565 (M + H) 265 IVb thiomorpholine HCl

4 498 (M + H) 266 IVb N-methyl- propargylamine

4 464 (M + H) 267 IVb N-methyl-β- alaninenitrile

4 479 (M + H) 268 IVb 1-methyl-4- (methyl- amino)piperidine

4 523 (M + H) 269 IVb 2-ethyl- piperidine

4 508 (M + H) 270 IVb 1-piperazine- carboxaldehyde

4 509 (M + H) 271 IVb 2-piperidim- ethanol

4 524 (M + H) 272 IVb 2-(methylamino)- ethanol

4 470 (M + H) 273 IVb N-methylallyl- amine

4 466 (M + H) 274 IVb 2-(piperidino- methyl)- piperidine

4 577 (M + H) 275 IVb 1-(1-phenyl- ethyl)- piperazine

4 585 (M + H) 276 IVb 1-(2-phenyl- ethyl)- piperazine

4 585 (M + H) 277 IVb N,N-dimethyl- N′-ethylene- diamine

4 511 (M + H) 278 IVb N,N-diethyl-N- methylene- ethylenediamine

4 525 (M + H) 279 IVb 1-cyclohexyl- piperazine

4 563 (M + H) 280 IVb 2,6-dimethyl- piperidine

4 508 (M + H)

EXAMPLES 281-288

The following hydroxamic acids were sythesized from Resin IX using Step10 with the indicated boronic acid, followed by cleavage from thepolymer using Step 3, as discussed previously for Example 213-232:

Example MS (ES) Number Boronic acid R m/z 281 4-methoxy- benzeneboronicacid

392 (M + H) 282 3-methoxy- benzeneboronic acid

392 (M + H) 283 4-methylthio- benzeneboronic acid

408 (M + H) 284 4-MeNHSO₂— benzene boronic acid

455 (M + H) 285 4-carboxy- benzene- boronic acid

406 (M + H) 286 2-trifluoro- methylbenzene- boronic acid

430 (M + H) 287 3,5-bis- (trifluoro- methyl)- benzeneboronic acid

498 (M + H) 288 2,3,4-trifluoro- benzeneboronic acid

416 (M + H)

EXAMPLES 289-294

Step 11: Preparation of Resin XI.

Into a fritted reaction vessel was placed Resin IIIc (50 mg, 0.043mmol). A 0.43 M solution of the isocyanate in 1-methyl-2-pyrrolidinone(1 mL, 0.43 mmol) was added followed by diisopropylethylamine (75 uL,0.43 mmol). The vessel was capped under nitrogen, agitated on a tabletopshaker, and heated to 50 degrees Celsius for 48 hours. Then, the vesselwas cooled to room temperature, and the resin was drained and washedwith 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water,water, 1:9 acetic acid/water, methanol and methylene chloride (3×1 mLeach solvent).

The following hydroxamic acids were synthesized from Resin IIIc usingStep 11 with the indicated isocyanate, followed by release from thepolymer using the reaction conditions in Step 3.

Example MS (FAB) Number Isocyanate R m/z 289 phenyl isocyanate

489.1 (M + H) 290 4-fluorophenyl isocyanate

507.2 (M + H) 291 4-phenoxyphenyl isocyanate

581.3 (M + H) 292 4-butoxyphenyl isocyanate

561.4 (M + H) 293 4-phenylphenyl- isocyanate

565.2 (M + H) 294 α,α,α-trifluoro m-tolyl ioscyanate

557.2 (M + H)

EXAMPLES 295-300

Step 12: Synthesis of Resin XII.

Into a fritted reaction vessel was placed resin VII (50 mg, 0.038 mmol)and cesium carbonate (122 mg, 0.38 mmol). A 0.43 M solution of thephenol in 1-methyl-2-pyrrolidinone (1 mL, 0.43 mmol) was added, then thevessel was capped under nitrogen. The reaction mixture was agitated on atabletop shaker and heated to 50 degrees Celsius for 48 hours. Then, thevessel was cooled to room temperature, and the resin was drained andwashed with 1-methyl-2-pyrrolidinone, 1:11-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanoland methylene chloride (3×1 mL each solvent).

The following hydroxamic acids were synthesized from Resin IIIc usingStep 11 with the indicated isocyanate, followed by release from thepolymer using the reaction conditions in Step 3.

Exam- ple MS (FAB) Number Phenol R m/z 295 phenol

490 (M + H) 296 3-methoxy- phenol

520 (M + H) 297 4-chloro- phenol

524.1 (M + H) 298 p-cresol

504.3 (M + H) 299 4-phenyl- phenol

566.3 (M + H) 300 4-hydroxy- diphenyl- methane

580.2 (M + H)

EXAMPLES 301-323 Large Scale Preparation of Resin Xa

A fritted reaction vessel was charged with Resin IX (1 g, 0.86 mmol) anda 0.008 M solution of tetrakis-(triphenylphosphine)palladium(0) inethylene glycol dimethyl ether (5 mL, 0.04 mmol). A 1 M solution of2-formylbenzeneboronic acid in a 1:1 mixture of ethanol and ethyleneglycol dimethyl ether (6 mL, 6 mmol) was added followed by 1 M cesiumcarbonate in water (2 mL, 2 mmol). The vessel was sealed under argon andheated to 90 degrees Celsius for 16 hours. After this, the vessel wascooled to room temperature, and the resin drained and washed with thefollowing sequence of solvents dimethylformamide, 1:1dimethylformamide/water, dimethylformamide, water, methanol, methylenechloride (3×5 mL each solvent). The resin was dried in vacuo to yield1.025 g of product as a tan polymeric solid. The theoretical loading ofthe polymer was 0.84 mmol/g. TFA cleavage performed on 35 mg of Resin Xaas described in Step 3 yielded 11.2 mg of a tan solid

Large Scale Preparation of Resin Xb

Preparation of Resin Xb followed the identical procedure described forpreparation of resin Xa, except 3-formylbenzeneboronic acid wassubstituted for 2-formylbenzeneboronic acid. The yield after drying invacuo was 1.052 g of Resin Xb as tan resin beads. The theoreticalloading of the polymer was 0.84 mmol/g. TFA cleavage performed on 20 mgof Resin Xb as described in Step 3 yielded 6.5 mg of a tan solid.

Large Scale Preparation of Resin Xc

Preparation of Resin Xc followed the identical procedure described forpreparation of resin Xa, except 4-formylbenzeneboronic acid wassubstituted for 2-formylbenzeneboronic acid. The yield after drying invacuo was 1.03 g of Resin Xc as tan resin beads. The theoretical loadingof the polymer was 0.84 mmol/g. TFA cleavage performed on 28 mg of ResinXb as described in step 3 yielded 9.4 mg of a tan solid.

Step 13: Synthesis of Resin XIII.

Into a fritted reaction vessel was placed resin Xa, Xb or Xc (50 mg,0.042 mmol). A 0.2 M solution of the amine in trimethylorthoformate (1mL, 0.2 mmol) was added, and the vessel was capped under nitrogen. Thereaction mixture was agitated on a tabletop shaker for 3 hours. Then, a0.5 M solution of sodium triacetoxyborohydride in1-methyl-2-pyrrolidinone (0.8 mL, 0.4 mmol) was added to the vessel, andthe mixture was agitated an additional 40 hours. After this, the resinwas drained and washed (3×1 mL each solvent) with the following sequenceof solvents: 1-methyl-2-pyrrolidinone, methanol, water, methanol andmethylene chloride.

The following hydroxamic acids were synthesized using the indicatedresin-bound aldehyde and the indicated amine following the procedureoutlined in Step 13 followed by release from the polymer using theprocedure in Step 3:

Example MS (ES) Number Resin Amine R position m/z 301 Xb 1,2,3,4-tetrahydro- isoquinoline

3 507 (M + H) 302 Xb 1-methyl- piperazine

3 474 (M + H) 303 Xb piperazine

3 460 (M + H) 304 Xb benzylamine

3 481 (M + H) 305 Xb propylamine

3 433 (M + H) 306 Xb ethyl iso- nipecotate

3 531 (M + H) 307 Xa benzylamane

2 481 (M + H) 308 Xa isopropyl- amine

2 433 (M + H) 309 Xa 1,2,3,4- tetrahydro- isoquinoline

2 507 (M + H) 310 Xa 1-methyl- piperazine

2 474 (M + H) 311 Xc piperidine

4 459 (M + H) 312 Xc morpholine

4 461 (M + H) 313 Xc 1-methyl- piperazine

4 474 (M + H) 314 Xc 1-phenyl- piperazine

4 536 (M + H) 315 Xc 1-benzyl- piperazine

4 550 (M + H) 316 Xc 1-(4-fluoro- phenyl)- piperazine

4 554 (M + H) 317 Xc N,N,N′- trimethyl- ethylenediamine

4 476 (M + H) 318 Xc hexamethyl- eneimine

4 473 (M + H) 319 Xc 1-methyl- homopiperazine

4 488 (M + H) 320 Xc diethylamine

4 447 (M + H) 321 Xc pyrrolidine

4 445 (M + H) 322 Xb dimethylamine

3 419 (M + H) 323 Xc 1-t-butoxy- carbonyl- piperazine

4 460 (M + H)

Large Scale Preparation of Resin Xd

Preparation of Resin Xd followed the identical procedure described forpreparation of resin Xa, except 4-carboxybenzeneboronic acid wassubstituted for 2-formylbenzeneboronic acid. The yield after drying invacuo was 1.07 g of Resin Xd as a tan polymeric solid. The theoreticalloading of the polymer was 0.83 mmol/g. TFA cleavage performed on 23.5mg of Resin Xd as described in Step 3 yielded 4.9 mg of a tan solid.

Step 14: Synthesis of Resin XIV

Into a fritted reaction vessel was placed resin Xd (50 mg, 0.042 mmol).The resin was washed with 1-methyl-2-pyrrolidinone (2×3 mL), then a 1.0M solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate in 1-methyl-2-pyrrolidinone (0.2 mL, 0.2 mmol) wasadded, followed by a 0.7 M solution of the amine in1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) and a 1.0 M solution of thediisopropylethylamine in 1-methyl-2-pyrrolidinone (0.4 mL, 0.4 mmol).The vessel was capped under nitrogen, and the reaction mixture wasagitated on a tabletop shaker for 24 hours. Then, the resin was drainedand washed with 1-methyl-2-pyrrolidinone (3×1 mL). The reaction with theamine was repeated by addition of a 1.0 M solution ofbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphatein 1-methyl-2-pyrrolidinone (0.2 mL, 0.2 mmol), a 0.7 M solution of theamine in 1-methyl-2-pyrrolidinone (0.3 mL, 0.21 mmol) and a 1.0 Msolution of the diisopropylethylamine in 1-methyl-2-pyrrolidinone (0.4mL, 0.4 mmol). The vessel was capped under nitrogen, and the reactionmixture was agitated an additional 8 hours. Then, the resin was drainedand washed with the following sequence of solvents:1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9acetic acid/water, methanol, methylene chloride (3×1 mL each solvent).

The following hydroxamic acids were synthesized using Resin Xd and theindicated amine following the procedure outlined in Step 14 followed byrelease from the polymer using the procedure in Step 3:

Exam- MS (ES) ple amine R m/z 324 propylamine

447 (M + H) 325 piperidine

473 (M + H) 326 morpholine

475 (M + H) 327 1-methyl- piperazine

488 (M + H) 328 diethylamine

461 (M + H) 329 pyrrolidine

459 (M + H) 330 ethyl isonipecotate

545 (M + H) 331 1-phenyl- piperazine

550 (M + H) 332 ethyl nipecotate

545 (M + H) 333 1-benzyl- piperazine

564 (M + H) 334 3,5- dimethyl- piperidine

501 (M + H) 335 thio- morpholine hydro- chloride

491 (M + H)

EXAMPLE 336 Preparation of4-[[4-[4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1-piperidinyl]-phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid

Part A: To a solution of the product of Example 11, Part B (10.0 g, 34.7mmol) in 1-methyl-2-pyrrolidinone (70 mL) was added4-(N-t-butoxycarbonylamino)piperidine (10.43 g, 52.1 mmol), followed bydiisopropylethylamine (6.0 mL, 34.7 mmol). The resulting mixture washeated at 80 degrees Celsius for 24 hours and then cooled to roomtemperature. The crude mixture was poured into 700 mL water, and thecloudy aqueous layer was extracted with ethyl acetate (3×150 mL). Thecombined organic layers were washed with 5% potassium hydrogen sulfate(2×150 mL) and brine (2×150 mL), dried over magnesium sulfate, andconcentrated in vacuo to give the crude. ester as a white foamy solid(13.04 g, 78%).

Part B: To a solution of the ester of part A (5.74 g, 11.9 mmol) in amixture of ethanol (80 mL) and tetrahydrofuran (40 mL) was added 2 Nsodium hydroxide (60 mL; 120 mmole). The resulting solution was heatedto 60 degrees Celsius for 1 hour and then cooled to room temperature.The solution was concentrated in vacuo, and the residue was partitionedbetween water (300 mL) and ethyl acetate (200 mL). The aqueous layer wasseparated and acidified with concentrated hydrogen chloride to pH 2. Awhite precipitate formed, which was collected by vacuum filtration anddried in vacuo to give the carboxylic acid as a white solid (4.88 g,88%).

Part C: To a suspension of the carboxylic acid from part B (4.88 g, 10.4mmol) in methylene chloride (35 mL) was added trifluoroacetic acid (35mL), resulting in dissolution of the solid. After fifteen minutes atambient temperature, the solution was concentrated in vacuo. The productwas triturated with diethyl ether to give the amino acid as an off-whitesolid (4.92 g, 98%).

Part D: A suspension of the amino acid from part C (4.92 g, 10.21 mmol)in a mixture of 10% sodium carbonate/water (35 mL), water (100 mL) anddioxane (100 mL) was cooled in an ice bath. To the cooled suspension isadded a solution of 9-fluorenylmethylsuccinimidyl carbonate (3.79 g,11.23 mmol) in dioxane (50 mL) dropwise. After complete addition, theice bath was removed, and the mixture warmed to room temperature. Afterone hour, the solution was concentrated in vacuo, and the residue waspartitioned between water (300 mL) and ethyl acetate (200 mL). Theaqueous layer was separated and acidified with concentrated hydrogenchloride to pH 2. The white precipitate formed, which was collected byvacuum filtration, washed with hexanes and dried in vacuo to give thetitle compound as a white solid (5.46 g, 91%).

Step 15: Preparation of Resin XVI.

Part A: Following the procedure outlined in Step 1 above, the product ofExample 336 (2.4 g, 4.06 mmol) was reacted with Resin I (1.7 g, 2.03mmol) to give Resin XV as a tan polymeric solid (2.82 g). Theoreticalloading on polymer was 0.71 mmol/g.

Part B: Resin XV from part A above (2.76 g, 1.96 mmol) was suspended ina 1:4 piperidine/dimethylformamide solution (20 mL) in a frittedreaction vessel and agitated on a tabletop shaker for 5 minutes. Theresin was drained, and an additional volume of a 1:4 mixture ofpiperidine/dimethylformamide (20 mL) was added to the vessel. The slurrywas agitated at room temperature for 30 minutes. After this, the resinwas drained and washed with dimethylformamide, methanol, and methylenechloride (3×20 mL each solvent). After drying in vacuo, the title resinwas obtained as a tan polymeric solid (2.30 g).

Step 16: Acylation/Sulfonylation of Resin XVI.

In a fritted reaction vessel, Resin XVI (50 mg, 0.043 mmol) was washedwith 1-methyl-2-pyrrolidinone (2×1 mL). Then, a 0.22 M solution of theacylating or sulfonylating reagent in 1-methyl-2-pyrrolidinone (1 mL,0.22 mmol) was added to the resin followed by diisopropylethylamine (40uL, 0.22 mmol). The vessel was capped under nitrogen and agitated on atabletop shaker at room temperature for 16 hours. Then, the resin wasdrained and washed with 1-methyl-2-pyrrolidinone, water, 1:9 aceticacid/water, methanol and methylene chloride (3×1 mL each solvent).

The following hydroxamic acids were synthesized from Resin XVI usingStep 16 with the indicated acylating or sulfonylating reagent, followedby release from the polymer using the reaction conditions in Step 3.

Acylating or MS (ES) Example Sulfonylating Reagent R m/z 337 benzoylchloride

  488.2 (M + H) 338 nicotinyl chloride-HCl

  489.2 (M + H) 339 benzenesulfonyl chloride

462 (M + H) 340 1-methyl- imidazole-4- sulfonyl chloride

  528.2 (M + H) 341 acteyl chloride

  426.2 (M + H) 342 methanesulfonyl chloride

  462.1 (M + H) 343 cyclohexyl isocyanate

509 (M + H) 344 2-methoxyphenyl isocyanate

533 (M + H) 345 phenyl isocyanate

503 (M + H) 346 beta-phenylethyl isocyanate

531 (M + H) 347 isopropyl isocyanate

469 (M + H) 348 4-fluorophenyl isocyanate

521 (M + H) 349 4-(methylthio)- phenyl isocyanate

549 (M + H) 350 4-phenoxyphenyl isocyanate

595 (M + H) 351 4-phenylphenyl isocyanate

579 (M + H) 352 benzyl isocyanate

517 (M + H) 353 ethyl isocyanate

455 (M + H) 354 alpha,alpha,alpha- trifluoro-m-tolyl isocyanate

571 (M + H) 355 ethyl 3-isocyanato- propionate

527 (M + H) 356 methyl oxalyl chloride

470 (M + H) 357 diethylcarbamyl chloride

483 (M + H) 358 dimethylcarbamyl chloride

455 (M + H) 359 diisopropyl carbamyl chloride

511 (M + H) 360 hydrocinnamoyl chloride

516 (M + H) 361 cinnamoyl chloride

514 (M + H) 361 isobutyl- chloroformate

484 (M + H) 363 benzylchloro- formate

518  (M + H), 364 trichloroethyl- chloroformate

558 (M + H)

EXAMPLES 365-371

Step 17: Reductive Alkylation of Resin XVI.

In a fritted reaction vessel, Resin XVI (50 mg, 0.043 mmol) was washedmethylene chloride (2×1 mL). Then, a 1 M solution of the aldehyde orketone in methylene chloride (1 mL, 1 mmol) was added to the resin. Thevessel was capped under nitrogen and agitated on a tabletop shaker atroom temperature for 3 hours. The resin was drained and washed withmethylene chloride (3×1 mL). Then, the resin was retreated with the 1 Msolution of the aldehyde or ketone in methylene chloride (1 mL, 1 mmol).The resin was drained and washed with methylene chloride (3×1 mL eachsolvent). Then, a 1 M solution of sodium triacetoxyborohydride in1-methyl-2-pyrrolidinone (1 mL, 1 mmol) was added to the resin, and thereaction was stirred overnight. After this, the resin was drained andwashed with 1-methyl-2-pyrrolidinone, methanol, water, 1:9 aceticacid/water, methanol and methylene chloride (3×1 mL each solvent).

The following hydroxamic acids were synthesized from Resin XVI usingStep 17 with the indicated aldehyde or ketone, followed by release fromthe polymer using the conditions in Step 3.

Example Aldehyde or MS (ES) Number Ketone R m/z 365 butyral- dehyde

440 (M + H) 366 acetone

426 (M + H) 367 N-propyl- 4-pyridone

509 (M + H) 368 4-t-butyl- cyclo- hexanone

522 (M + H) 369 2-pyridine- carbox- aldehyde

475 (M + H) 370 4′-(trifluoro- methoxy)- aceto- phenone

572 (M + H) 371 2- furaldehyde

464 (M + H)

EXAMPLE 372 Preparation of4-]]4-(4-butoxyphenoxy)-phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) indimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol)and 4-butoxyphenol (2.66 g, 16 mmol). The slurry was stirred at ninetyfive degrees Celsius for nineteen hours. The reaction was concentratedin vacuo. The residue was taken up in ethyl acetate, washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography(on silica, ethyl acetate/hexanes) provided the substituted THPhydroxamate as an off-white foam (3.96 g, 93%). HRMS (ES+) M+NH₄ ⁺calculated for C₂₇H₃₅N₁O₈S₁F: 551.24, found 551.24.

Part B: To a solution of the THP hydroxamate from part A (3.9 g, 7.3mmol) in 1,4-dioxane (20 mL) was added 4N HCl dioxane solution (20 mL)and methanol (20 mL). After fifteen minutes at ambient temperature thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (2.75 g, 84%). HRMS (ES+) M+H⁺ calculated for C₂₂H₂₇N₁O₇S₁:450.16, found 450.16.

EXAMPLES 373 Preparation oftetrahydro-N-hydroxy-4-[[4-[3-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) indimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol)and m-(trifluoromethyl)phenol (1.95 mL, 16 mmol). The slurry was stirredat ninety five degrees Celsius for nineteen hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP hydroxamate as a white foam (4.1 g, 97%). HRMS (ES+)M+H⁺ calculated for C₂₄H₂₆N₁O₇S₁F₃: 530.15, found 530.14.

Part B: To a solution of the THP hydroxamate from part A (3.9 g, 7.4mmol) in 1,4-dioxane (20 mL) was added 4N HCl dioxane solution (20 mL)and methanol (20 mL). After fifteen minutes at ambient temperature, thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (1.9 g, 58%). HRMS (ES+) M+H⁺ calculated for C₁₉H₁₈N₁O₆SF₃:446.09, found 446.09.

EXAMPLE 374 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(methylthio)phenoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (3.1 g, 8 mmol) indimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol)and 4-(methylthio)phenol (2.24 g, 16 mmol). The slurry was stirred atninety five degrees Celsius for twenty four hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP hydroxamate as a white foam (4.1 g, 100%). HRMS (ES+)M+H⁺ calculated for C₂₄H₂₉N₁O₇S₂: 508.15, found 508.15.

Part B: To a solution of the THP hydroxamate from part A (4.0 g, 7.9mmol) in 1,4-dioxane (20 mL) was added 4N HCl dioxane solution (20 mL)and methanol (20 mL). After fifteen minutes at ambient temperature, thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (1.9 g, 57%). HRMS (ES+) M+H⁺ calculated for C₁₉H₂₁N₁O₆S₂: 424.09,found 424.09.

EXAMPLE 375 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(phenylmethyl)phenoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (2.7 g, 7 mmol) indimethylacetamide (15 mL) was added cesium carbonate (6.84 g, 21 mmol)and 4-hydroxydiphenylmethane (2.8 g, 14 mmol). The slurry was stirred atninety degrees Celsius for nineteen hours. The reaction was concentratedin vacuo. The residue was taken up in ethyl acetate, washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography(on silica, ethyl acetate/hexanes) provided the substituted THPhydroxamate as a light yellow foam (3.7 g, 96%). HRMS (ES+) M+H⁺calculated for C₃₀H₃₃N₁O₇S₁: 552.21, found 552.21.

Part B: To a solution of the THP hydroxamate from part A (3.5 g, 6.4mmol) in 1,4-dioxane (16 mL) was added 4N HCl dioxane solution (16 mL)and methanol (16 mL). After fifteen minutes at ambient temperature thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (1.95 g, 67%). HRMS (ES+) M+H⁺ calculated for C₂₅H₂₅N₁O₆S₁:468.15, found 468.15.

EXAMPLE 376 Preparation oftetrahydro-N-hydroxy-4-[[4-(4-hydroxyphenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55) (2.7 g, 7 mmol) indimethylacetamide (20 mL) was added cesium carbonate (6.84 g, 21 mmol)and 4-(benzyloxy)phenol (2.8 g, 14 mmol). The slurry was stirred atninety five degrees Celsius for six hours. The reaction was concentratedin vacuo. The residue was taken up in ethyl acetate, washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography(on silica, ethyl acetate/hexanes) provided the substituted THPhydroxamate as a white foam (3.94 g, 99%). HRMS (ES+) M+NH₄ ⁺ calculatedfor C₃₀H₃₃N₁O₈S₁: 585.23, found 585.23.

Part B: To a solution of the THP hydroxamate from part A (1.5 g, 2.64mmol) in glacial acetic acid (5 mL) was added concentrated HCl (5 mL)and the reaction was heated to sixty degrees Celsius for twenty minutes.The reaction was cooled, diluted with water (100 mL) and extracted withethyl acetate. The ethyl acetate extract was washed with water threetimes, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.The product was recrystallized (acetone/hexanes) to give the titlecompound as a white solid (810 mg, 78%). HRMS (ES+) M+NH₄ ⁺ calculatedfor C₁₈H₁₉N₁O₇S₁: 468.15, found 468.15.

EXAMPLE 377 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-[(1-methylethyl)thio]phenoxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: To a suspension of 4-hydroxythiophenol (5.0 g, 40 mmol) andpotassium carbonate (8.0 g, 58 mmol) in dimethylformamide (70 mL) wasadded 2-iodopropane (7.0 g, 41 mmol). The slurry was stirred at ambienttemperature for one hour. The reaction was concentrated in vacuo. Theresidue was taken up in ethyl acetate, washed two times with water, 10%HCl solution, brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted phenol as a clear colorless oil (5.1 g, 76%).

Part B: To a solution of the product of Example 55 (3.1 g, 8 mmol) indimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol)and the phenol from part A (2.7 g, 16 mmol). The slurry was stirred atninety five degrees Celsius for fifteen hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP hydroxamate as a white foam (4.15 g, 97%). HRMS (ES+)M+H⁺ calculated for C₂₆H₃₃N₁O₇S₂: 536.18, found 538.17.

Part C: To a solution of the THP hydroxamate from part A (3.9 g, 7.3mmol) in 1,4-dioxane (18 mL) was added 4N HCl dioxane solution (18 mL)and methanol (18 mL). After fifteen minutes at ambient temperature, thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as an offwhite solid (2.32 g, 71%). HRMS (ES+) M+H⁺ calculated for C₂₁H₂₅N₁O₆S₂:452.12, found 452.12.

EXAMPLE 378 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-(1-methylethoxy)phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of benzoic acid, 4-hydroxyphenylester (8.57 g, 40mmol) in dimethylacetamide (65 mL) was added potassium carbonate (8.3 g,60 mmol) and 2-iodopropane (5 mL, 50 mmol). The slurry was stirred atsixty five degrees Celsius for one hour. The reaction was concentratedin vacuo. The residue was taken up in ethyl acetate, washed with waterthree times, brine, dried over Na₂SO₄, filtered, and concentrated invacuo to yield the isopropoxy compound as a light gray solid (9.7 g,95%).

Part B: To a slurry of the isopropoxy compound from part A (9.7 g, 38mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added 2.5N sodiumhydroxide solution (26 mL, 65 mmol). The slurry was stirred at sixtydegrees Celsius for four hours. The reaction was cooled and 6Nhydrochloric acid solution was added until the pH=5. The reaction wasextracted with methylene chloride. The organic layer was washed with 5%ammonium hydroxide solution four times, water, brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to yield the phenol as an amber oil(5.4 g, 94%).

Part C: To a solution of the product of Example 55 (3.1 g, 8 mmol) indimethylacetamide (20 mL) was added cesium carbonate (7.28 g, 24 mmol)and the phenol from part B (2.4 g, 16 mmol). The slurry was stirred atninety five degrees Celsius for twenty one hours. The reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith water three times, brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the substituted THP hydroxamate as an off white foam (3.65 g,88%). HRMS (ES+) M+H⁺ calculated for C₂₆H₃₃N₁O₉S₁: 520.20, found 520.20.

Part D: To a solution of the THP hydroxamate from part C (3.5 g, 6.7mmol) in 1,4-dioxane (17 mL) was added 4N HCl dioxane solution (17 mL)and methanol (17 mL). After fifteen minutes at ambient temperature, thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as an offwhite solid (2.2 g, 80%). HRMS (ES+) M+H⁺ calculated for C₂₁H₂₅N₁O₇S₁:436.14, found 436.14.

EXAMPLE 379 Preparation oftetrahydro-N-hydroxy-4-[[4-[4-[(trifluoromethyl]phenoxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: In dry equipment under nitrogen, sodium hydride (60% oildispersion) (11 g, 0.275 mol) was added to a solution of4-[4-(trifluoromethyl)phenoxyl-phenol (50.0 g, 0.197 mol) in drydimethylformamide (150 mL) at zero degrees Celsius. After fifteenminutes, a solution of dimethylthiocarbamoyl chloride (32.0 g, 0.259mol) in dry dimethylformamide (100 mL) was added. The reaction wasstirred at ambient temperature for sixteen hours. The reaction waspoured onto 10% hydrochloric acid solution (1 L). Vacuum filtration ofthe resulting precipitate provided the thiono compound as a white solid(67.0 g, 100%).

Part B: The thiono compound from part A (70 g, 0.2 mol) was heated tothree hundred seventeen degrees Celsius for thirty minutes behind asafety shield. The reaction exothermed to three hundred thirty degreesCelsius. The heat was removed and the reaction came to ambienttemperature to yield the thiocarbamate as a brown solid (70 g, 100%).

Part C: To a solution of the thiocarbamate from part B (65.0 g, 0.19mol) in methanol (510 mL) with a subsurface nitrogen stream was added2.5N sodium hydroxide solution (160 mL, 0.4 mol). The slurry was stirredat seventy four degrees Celsius for two hours. The reaction was cooledand the methanol removed in vacuo. The residue was diluted with water(100 mL) and extracted with diethyl ether four times. A subsurfacestream of nitrogen was added to the aqueous solution and sodiumchloroacetate (22.2 g, 0.19 mol) was added. The reaction was stirred anambient temperature and after thirty minutes the nitrogen stream wasremoved. After twelve hours, the solution was cooled and 6N hydrochloricacid was added until the pH=1. The slurry was extracted with ethylacetate four times. The combined ethyl acetate extracts were washed with0.1N hydrochloric acid, water, brine, dried over Na₂SO₄ filtered anddried in vacuo to give the thioacetic acid as a tan solid (61.0 g, 98%).

Part D: To a solution of the thioacetic acid from part C (54.45 g, 0.166mol) in tetrahydrofuran (370 mL) was added water (45 mL) and Oxone® (306g, 0.498 mol) at twenty degrees Celsius. An exotherm to forty twodegrees Celsius was noted. After two hours, the reaction was filteredand the cake was washed well with tetrahydrofuran and then water (250mL) was added to the filtrate. The filtrate was concentrated in vacuo.The slurry was extracted with ethyl acetate four times. The combinedextracts were washed with water three times, brine, dried over MgSO₄,filtered, and concentrated in vacuo to give the sulfone as a beige solid(60.0 g, 100%).

Part E: A solution of the sulfone from part D (119.52 g, 0.332 mol) inmethanol (660 mL) and 4N hydrochloric acid in dioxane solution (20 mL)was stirred at ambient temperature for twelve hours. The reaction washeated to a boil and cooled slowly to ambient temperature. The resultingcrystals were filtered, washed well with cold methanol, and dried togive the methyl ester as a white solid (89.4 g, 72%).

Part F: To a solution of the methyl ester from part E (64.5 g, 0.180mol) in dimethylacetamide (360 mL) was added potassium carbonate (66.8g, 0.48 mol), bis-(2-bromoethyl)ether (40 mL, 0.305 mol),4-dimethylaminopyridine (1.1 g, 9 mmol), and tetrabutylammonium bromide(2.9 g, 9 mmol). The reaction was stirred overnight at ambienttemperature. The reaction was slowly poured into 1N HCl (500 mL). Theresulting precipitate was filtered, washed with water, then hexanes. Thesolid was recrystallized from methanol to give the pyran compound as awhite solid (62.8 g, 79%). MS (ES+) M+NH₄ ⁺ calculated forC₂₀H₁₉O₅₆S₁F₃: 462.12, found 462.12.

Part G: In dry equipment under nitrogen, the pyran compound from part F(64.0 g, 0.144 mol) was dissolved in dry tetrahydrofuran (250 mL) and asolution of potassium trimethylsilonate (55.9 g, 0.432 mol) in drytetrahydrofuran (40 mL) was added at ambient temperature. After twohours, water (200 mL) was added and the solution concentrated in vacuo.The slurry was extracted with ethyl acetate to remove unreacted startingmaterial. The aqueous solution was treated with 6N HCl until pH=1. Theslurry was extracted with ethyl acetate and the combined extracts washedwith water, brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was heated in diethyl ether, the resulting solidfiltered and dried to give the carboxylic acid as a white solid (56.3 g,91%). HRMS (ES+) M+NH₄ ⁺ calculated for C₁₉H₁₇O₆S₁F₃: 448.10, found448.10.

Part H: In dry equipment under nitrogen, the carboxylic acid from part G(49.0 g, 0.114 mol) was dissolved in dry dimethylformamide (280 ml) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (18.5 g, 0.137 mol),N-methylmorpholine (37.5 mL, 0.342 mol),O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (41.3 g, 0.353 mol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 30.6 g,0.160 mol). After four hours at ambient temperature, the reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith water, 5% KHSO₄, saturated NaHCO₃, brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to give the THP hydroxamate as awhite foam (62.6 g, 100%). HRMS (ES+) M+NH₄ ⁺ calculated forC₂₄H₂₆NO₇S₁F₃: 547.17, found 547.17.

Part I: To a solution of the THP hydroxamate from part H (58.5 g, 0.11mol) in 1,4-dioxane (280 mL) was added 4N HCl dioxane solution (280 mL)and methanol (280 mL). After fifteen minutes at ambient temperature, thereaction was diluted with ethyl acetate and washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo. The product wasrecrystallized (acetone/hexanes) to give the title compound as a whitesolid (42.79 g, 87%) HRMS (ES+) M+NH₄ ⁺ calculated for C₁₉H₁₈NO₆S₁F₃:463, found 463.

EXAMPLE 380 Preparation of4-[[4-([1,1′-biphenyl]-4-yloxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) indimethylacetamide (8 mL) was added 4-phenylphenol (Aldrich, 1.3 g, 7.8mmol) followed by cesium carbonate (6.8 g, 20.8 mmol). The reaction washeated at ninety-five degrees Celsius for five hours. Stripping thedimethylacetamide in vacuo afforded a brown solid (5.3 g, quantitative).Chromatography (reverse phase, C-18, acetonitrile/water) gave theTHP-protected biphenyl product in solution.

Part B: To the collected THP-protected diphenyl product from A inacetonitrile/water (50 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about eighteen hours), the acetonitrile wasstripped. The resultant precipitate was collected, giving the titlecompound as a white solid (2.0 g, 83%). MS (FAB) M⁺H calculated forC₂₄H₂₃NO₆S: 454, found 454.

EXAMPLE 381 Preparation oftetrahydro-N-hydroxy-4-[[4-[[4-(trifluoromethyl)phenyl]thio]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) indimethylacetamide (6 mL) was added 4-trifluoromethylthiophenol(Maybridge, 2.0 g, 11.2 mmol), followed by potassium carbonate (2.9 g,20.8 mmol). The reaction was heated at sixty-five degrees Celsius fortwelve hours. Stripping the dimethylacetamide in vacuo afforded a brownsolid (6.5 g, quantitative). Chromatography (reverse phase, C-18,acetonitrile/water) gave the THP-protected trifluoromethyl product insolution.

Part B: To the solution of the crude THP-protected trifluoromethylproduct from in acetonitrile/water (40 mL) was slowly added 10% HCl_(aq)(100 mL). After stirring overnight (about eighteen hours), theacetonitrile was stripped. The resultant precipitate was collected,giving the title compound as a tan solid (0.75 g, 31%). MS (FAB) M⁺Hcalculated for C₁₉H₁₈F₃NO₅S₂: 462, found 462.

EXAMPLE 382 Preparation ofTetrahydro-N-hydroxy-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) indimethylacetamide (6 mL) was added 4-(trifluoromethylthio)thiophenol(Aldrich, 1.5 g, 7.8 mmol) followed by cesium carbonate (6.8 g, 20.8mmol). After adding a catalytic amount of potassium fluoride, thereaction was heated at ninety-five degrees Celsius for twelve hours.Stripping the dimethylacetamide in vacuo afforded a brown solid (7.2 g,quantitative). Chromatography (reverse phase, C-18, acetonitrile/water)gave the THP-protected trifluoromethylthio product in solution.

Part B: To the solution of the crude THP-protected trifluoromethylthioproduct from A in acetonitrile/water (40 mL) was slowly added 10%HCl_(aq) (100 mL). After stirring overnight (about eighteen hours), theacetonitrile was stripped. The resultant precipitate was collected,giving the title compound as a tan solid (0.60 g, 24%). MS (FAB) M⁻Hcalculated for C₁₉H₁₈F₃NO₆S₂: 476, found 476.

EXAMPLE 380 Preparation of4-[[4-[4-chloro-3-(trifluoro-methyl)phenoxy]phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (2.0 g, 5.2 mmol) indimethylacetamide (6 mL) was added 4-chloro-3-trifluoromethylphenol(Avocado, 1.5 g, 7.8 mmol) followed by cesium carbonate (6.8 g, 20.8mmol). The reaction was heated at ninety-five degrees Celsius for twelvehours. Stripping the dimethylacetamide in vacuo afforded a brown solid(7.6 g, quantitative). Chromatography (reverse phase, C-18,acetonitrile/water) gave the THP-protected product in solution.

Part B: To the solution of the crude THP-protected product from inacetonitrile/water (40 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about eighteen hours), the acetonitrile wasstripped. The resultant precipitate was collected, giving the titlecompound as a white solid (0.92 g, 37%). MS (FAB) M⁺H calculated forC₁₉H₁₇ClF₃NO₆S: 480, found 480.

EXAMPLE 384 Preparation of4-[[4-[4-(1,1-dimethylethyl)-phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (5.0 g, 12.9 mmol) indimethylacetamide (25 mL) was added 4-t-butylphenol (Avocado, 2.9 g,19.4 mmol) followed by cesium carbonate (20.4 g, 20.862.5 mmol). Thereaction was heated at ninety-five degrees Celsius for twelve hours.Stripping the dimethylacetamide in vacuo afforded a brown solid (9.4 g,quantitative). Chromatography (reverse phase, C-18, acetonitrile/water)gave the THP-protected product in solution.

Part B: To the solution of the crude THP-protected product from inacetonitrile/water (60 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about eighteen hours), the acetonitrile wasstripped. The resultant precipitate was collected, giving the titlecompound as a white solid (0.28 g, 5 MS (FAB) M⁺H calculated forC₂₂H₂₇NO₆S: 434, found 434.

EXAMPLE 385 Preparation of4-[[4-[3,5-bis(trifluoromethyl)phenoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (3.0 g, 7.7 mmol) indimethylacetamide (15 mL) was added 3,5-ditrifluoromethylphenol (2.9 g,19.4 mmol) followed by cesium carbonate (20.4 g, 20.862.5 mmol). Thereaction was heated at ninety-five degrees Celsius for twelve hours.Stripping the dimethylacetamide in vacuo afforded a brown solid (14.7 g,quantitative). Chromatography (reverse phase, C-18, acetonitrile/water)gave the THP-protected product in solution.

Part B: To the solution of the crude THP-protected product from inacetonitrile water (60 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about eighteen hours), the acetonitrile wasstripped. The resultant precipitate was collected, giving the titlecompound as a white solid (1.2 g, 31%). MS (FAB) M⁺H calculated forC₂₀H₁₇F₆NO₆S: 514, found 514.

EXAMPLE 386 Preparation oftetrahydro-N-hydroxy-4-[[4-[3-methyl-4-(1-methylethyl)phenoxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (4.0 g, 10.3 mmol) indimethylacetamide (20 mL) was added 4-isopropyl-3-methylphenol (Aldrich,2.3 g, 15.5 mmol) followed by cesium carbonate (16.8 g, 51.5 mmol). Thereaction was heated at ninety-five degrees Celsius for twelve hours.Stripping the dimethylacetamide in vacuo afforded a brown solid (18.3 g,quantitative). Chromatography (reverse phase, C18, acetonitrile/water)gave the THP-protected product in solution.

Part B: To the solution of the crude THP-protected product from A inacetonitrile/water (40 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about eighteen hours), the acetonitrile wasstripped. The resultant precipitate was collected, giving the titlecompound as a tan solid (1.8 g, 40%). MS (FAB) M⁻H calculated forC₂₂H₂₇F₃NO₆S: 432, found 432.

EXAMPLE 387 Preparation ofTetrahydro-N-hydroxy-4-[[4-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A: To a solution of the product of Example 55 (5.0 g, 12.9 mmol) indimethylacetamide (25 mL) was added2,2,3,3-tetrafluoro-6-hydroxybenzodioxene (Oakwood, 4.3 g, 19.4 mmol)followed by cesium carbonate (21.0 g, 64.5 mmol). The reaction washeated at ninety-five degrees Celsius for five hours. Stripping thedimethylacetamide in vacuo afforded a brown solid (11.3 g, quantitative)chromatography (reverse phase, C-18, acetonitrile/water) gave theTHP-protected product in solution.

Part B: To the collected THP-protected product from A inacetonitrile/water (50 mL) was slowly added 10% HCl_(aq) (100 mL). Afterstirring overnight (about eighteen hours), the acetonitrile wasstripped. The resultant precipitate was collected, giving the titlecompound as a white solid (3.5 g, 54%). MS (FAB) M⁻H calculated forC₂₀H₁₇F₄NO₈S: 506, found 506.

EXAMPLE 388 Preparation ofN-hydroxy-1-[2-(4-morpholinyl)-ethyl]-4-[[4-(4-(trifluoromethyl)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0 g,0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol),which was added in several portions. The resulting mixture was stirredat ambient temperature for 22 hours then filtered and concentrated invacuo. The solids were washed with hexanes and then collected byfiltration to give the Boc-piperidine compound as an amber oil (124 g,>100%).

Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone(400 mL), degassed with N₂, was added Cs₂CO₃ (159 g, 0.488 mol). Afterdegassing the resulting mixture with N₂ for 5 minutes, theBoc-piperidine compound of part A (85.9 g, 0.325 mol) was added. Theresulting mixture was stirred at ambient temperature for 18 hours andthen filtered through a pad of Celite®, washing with acetone. Thefiltrate was concentrated in vacuo to provide the sulfide as a tanresidue (98.5 g, 97%).

Part C: To a solution of the sulfide of part B (8.00 g, 25.7 mmol) indichloromethane (90 mL) and methanol (15 mL) was addedmonoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol)in two portions. The resulting mixture was stirred at ambienttemperature for 1.5 hours and then filtered. The filtrate was washedwith saturated NaHCO₃ and then with saturated NaCl. The combined aqueouslayers were extracted with dichloromethane (100 mL). The combinedorganic layers were dried over Na₂SO₄ and then concentrated in vacuo.The resulting solids were washed with hexanes then dissolved indichloromethane and filtered through a pad of Celite®, washing withdichloromethane. The filtrate was concentrated in vacuo andrecrystallization from ethyl acetate provided the sulfone as a whitecrystalline solid (4.45 g, 50%).

Part D: To a solution of sulfone of part C (7.00 g, 20.4 mmol) inN,N-dimethylformamide (40 mL) was added Cs₂CO₃ (19.9 g, 61.2 mmol) andα,α,α-trifluoro-p-cresol (3.97 g, 24.5 mmol). The resulting mixture washeated at eighty degrees Celsius for 16 hours. After cooling to ambienttemperature the reaction mixture was concentrated in vacuo. Theresulting residue was treated with H₂O and the solids were collected byfiltration. The solids were then washed with hexanes then methanol toprovide the biaryl ether as a tan solid (8.60 g, 87%).

Part E: To a solution of the biaryl ether of part D (8.59 g, 17.7 mmol)in tetrahydrofuran (100 mL), cooled to zero degrees Celsius, was slowlyadded lithium bis(trimethylsilyl)amide (22.0 mL, 1.0M intetrahydrofuran, 22.0 mmol), at such a rate that the temperature of thereaction never exceeded one degree Celsius. The resulting mixture wasstirred at zero degrees Celsius for 1 hour then a solution of methylchloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) wasslowly added, at such a rate that the temperature of the reactionmixture never exceeded four degrees Celsius. After the addition wascomplete, the mixture was slowly permitted to warm to ambienttemperature. Saturated NH₄Cl (50 mL) was added and the tetrahydrofuranwas removed in vacuo. Water (50 mL) was added to the residue which wasthen extracted with ethyl acetate. The combined organic layers werewashed with saturated NaCl and dried over Na₂SO₄. Recrystallization frommethanol provided the methyl ester as a pale yellow crystalline solid(7.66 g, 80%).

Part F: To a solution of the methyl ester of part E (7.66 g, 14.1 mmol)in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HClin dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2hours additional 4N HCl in dioxane (10 mL, 40 mmol) was added. Afterstirring at ambient temperature for 2.5 hours, the reaction mixture wasconcentrated in vacuo to provide the amine as an off-white solid (6.80g, >100%).

Part G: To a suspension of the amine of part F (3.00 g, 6.25 mmol) inacetonitrile (20 mL) was added K₂CO₃ (3.46 g, 25.0 mmol),4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and acatalytic amount of NaI. The resulting mixture was heated at reflux for22 hours. After cooling to ambient temperature, the reaction mixture wasfiltered through a pad of Celite®, washing with ethyl acetate. Thefiltrate was concentrated in vacuo to provide the morpholinyl ethylamine as a tan solid (3.45 g, >100%).

Part H: To a solution of the morpholinyl ethyl amine of part G (3.45 g,6.25 mmol) in tetrahydrofuran (60 mL) was added potassiumtrimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambienttemperature for 25 hours, H₂O was added. The reaction mixture was thenneutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuoand the resulting precipitate was collected by filtration and washedwith diethyl ether to provide the amino acid as an off-white solid (2.87g, 85%).

Part I: To a suspension of the amino acid of part H (2.87 g, 5.29 mmol)in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9mmol), O-(tetrahydropuranyl)hydroxylamine (0.682 g, 5.82 mmol) andPyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for19 hours additional N-methylmorpholine (0.872 mL, 7.94 mmol),O-(tetrahydropuranyl)hydroxylamine (0.310 g, 2.65 mmol) and PyBroP®(1.48 g, 3.17 mmol) were added. The resulting mixture was stirred atambient temperature for 3 hours and then concentrated in vacuo. Theresidue was partitioned between ethyl acetate and H₂O. The organiclayers were washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, methanol/chloroform) provided the protectedhydroxamate as an off-white solid (2.62 g, 77%).

Part J: To a solution of the protected hydroxamate of part I (2.62 g,4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirredat ambient temperature for 2 hours and then diethyl ether (20 mL) wasadded. The resulting solids were collected by filtration to give thetitle compound as an off-white solid (2.31 g, 90%). MS MH⁺ calculatedfor C₂₅H₃₁O₆N₃SF₃: 558, found 558.

EXAMPLE 389 Preparation ofN-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

Part A: To a suspension of the amine of part F, Example 388 (1.50 g,3.13 mmol) in acetonitrile (10 mL) were added K₂CO₃ (1.73 g, 12.5 mmol)and 4-picolyl chloride hydrochloride (0.565 g, 3.44 mmol). Afterstirring at reflux for 21.5 hours, the reaction mixture was filteredthrough a pad of Celite®, washing with ethyl acetate. The filtrate wasconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the picolyl amine as a clear gum (1.44 g, 86%).

Part B: To a solution of the picolyl amine of part A (1.44 g, 2.69 mmol)in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate(0.690 g, 5.38 mmol). The resulting mixture was stirred at ambienttemperature for 20 hours and then the tetrahydrofuran was removed byblowing N₂ over the reaction mixture water (8 mL) was added and thereaction mixture was neutralized (pH 7) with 2N HCl. The resultingprecipitate was collected by filtration to provide the amino acid as awhite solid (1.31 g, 94%).

Part C: To a suspension of the amino acid of part B (1.31 g, 2.52 mmol)in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.408g, 3.02 mmol), N-methylmorpholine (0.831 mL, 7.56 mmol),O-(tetrahydropuranyl)hydroxylamine (0.443 g, 3.78 mmol) and1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.676 g,3.53 mmol). The resulting mixture was stirred at ambient temperature for3 days then concentrated in vacuo. The residue was partitioned betweenH₂O and ethyl acetate. The combined organic layers were washed withsaturated NaHCO₃, saturated NaCl and dried over Na₂SO₄. Chromatography(on silica, ethyl acetae/hexanes) provided the protected hydroxamate asa white foam (1.24 g, 79%).

Part D: To a solution of the protected hydroxamate of part C (1.24 g,2.00 mmol) in dioxane (6 mL) and methanol (2 mL) was added a solution of4N HCl in dioxane (5.00 mL, 20.0 mmol). After stirring at ambienttemperature for 2.5 hours the reaction mixture was concentrated invacuo. The resulting foam was then treated again with a solution of 4NHCl in dioxane (3 mL) for 15 minutes then diethyl ether was added andthe resulting precipitate was collected by filtration to provide thetitle compound as an off-white solid (1.04 g, 85%). MS MH⁺ calculatedfor C₂₅H₂₅O₅N₃SF₃: 536, found 536.

EXAMPLE 390 Preparation ofN-hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

Part A: To a suspension of the amine of part F, Example 388 (1.00 g,2.08 mmol) in acetonitrile (10 mL) was added K₂CO₃ (1.15 g, 8.33 mmol)and 3-picolyl chloride hydrochloride (0.375 g, 2.29 mmol). Afterstirring at reflux for 12 hours the reaction mixture was filteredthrough a pad of Celite®, washing with ethyl acetate. The filtrate wasconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the picolyl amine as a pale yellow foam (0.740 g, 67%).

Part B: To a solution of the picolyl amine of part A (0.740 g, 1.38mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate(0.355 g, 2.77 mmol). The resulting mixture was stirred at ambienttemperature for 17 hours, then additional potassium trimethylsilanolate(0.044 g, 0.343 mmol) was added and the resulting mixture was stirred atambient temperature for 2 hours. The tetrahydrofuran was removed byblowing N₂ over the reaction mixture. Water (5 mL) was added and thereaction mixture was neutralized (pH 7) with 2N HCl. The resultingprecipitate was collected by filtration and dried by concentration invacuo with acetone to provide the amino acid as an off-white solid(0.700 g, 97%).

Part C: To a suspension of the amino acid of part B (0.700 g, 1.34 mmol)in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.218g, 1.61 mmol), N-methylmorpholine (0.442 mL, 4.02 mmol),O-(tetrahydropuranyl)hydroxylamine (0.235 g, 2.01 mmol) and1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.360 g,1.88 mmol). The resulting mixture was stirred at ambient temperature for23 hours, then concentrated in vacuo. The residue was partitionedbetween H₂O and ethyl acetate. The combined organic layers were washedwith H₂O, saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetae/hexanes) provided the protectedhydroxamate as an off-white foam (0.500 g, 60%).

Part D: To a solution of the protected hydroxamate of part C (0.500 g,0.807 mmol) in dioxane (1.5 mL) and methanol (0.5 mL) was added asolution of 4N HCl in dioxane (3.0 mL, 12.00 mmol). After stirring atambient temperature for 2 hours, diethyl ether was added and theresulting precipitate was collected by filtration to provide the titlecompound as a yellow solid (0.363 g, 74%). MS MH⁺ calculated forC₂₅H₂₅O₅SN₃SF₃: 536, found 536.

EXAMPLE 391 Preparation ofN-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

Part A: To a suspension of the amine of part F, Example 388 (1.26 g,2.63 mmol) in acetonitrile (10 mL) was added K₂CO₃ (1.45 g, 10.5 mmol)and 2-picolyl chloride hydrochloride (0.475 g, 2.89 mmol). Afterstirring at reflux for 12 hours, the reaction mixture was filteredthrough a pad of Celite®, washing with ethyl acetate. The filtrate wasconcentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes)provided the picolyl amine as an amber oil (1.40 g, 99%).

Part B: To a solution of the picolyl amine of part A (1.40 g, 2.62 mmol)in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate(0.672 g, 5.24 mmol). The resulting mixture was stirred at ambienttemperature for 15 hours. The tetrahydrofuran was removed by blowing N₂over the reaction mixture. H₂O (5 mL) was added and the reaction mixturewas neutralized (pH 7) with 2N HCl. The resulting precipitate wascollected by filtration and dried by concentration in vacuo withacetonitrile to provide the amino acid as an off-white solid (1.07 g,79%).

Part C: To a suspension of the amino acid of part B (1.07 g, 2.06 mmol)in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.333g, 2.47 mmol), N-methylmorpholine (0.679 mL, 6.18 mmol),O-(tetrahydropuranyl)hydroxylamine (0.362 g, 3.09 mmol) and1-3-1(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.553 g,2.88 mmol). The resulting mixture was stirred at ambient temperature for19 hours, then concentrated in vacuo. The residue was partitionedbetween H₂O and ethyl acetate. The combined organic layers were washedwith H₂O, saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, methanol/dichloromethane) provided theprotected hydroxamate as a white solid (1.03 g, 81%).

Part D: To a solution of the protected hydroxamate of part C (1.03 g,1.66 mmol) in dioxane (3.0 mL) and methanol (1.0 mL) was added asolution of 4N HCl in dioxane (3.0 mL, 12.00 mmol). After stirring atambient temperature for 1.5 hours, diethyl ether was added and theresulting precipitate was collected by filtration to provide the titlecompound as a pale pink solid (0.970 g, 96%). MS MH⁺ calculated forC₂₅H₂₅O₅N₃SF₃: 536, found 536.

EXAMPLE 392 Preparation ofN-hydroxy-4-[[4-[[4-methoxyphenyl)amino]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To the ester of part C, Example 91 (1.00 g, 2.17 mmol) was addedCs₂CO₃ (0.990 g, 3.04 mmol), BINAP (0.061 g, 0.098 mmol),tris(dibenzyldeneacetone)dipallidium(0) (0.060 g, 0.07 mmol),p-anisidine (0.320 g, 2.60 mmol) and toluene (4 mL). The resultingmixture was heated to one hundred degrees Celsius for 22 hours. Aftercooling to ambient temperature, diethyl ether was added and the mixturewas filtered through a pad of Celite®, washing with ethyl acetate. Thefiltrate was concentrated in vacuo. Chromatography (on silica, ethylacetate/hexane) provided the aniline as an orange foam (0.810 g, 74%).

Part B: To a solution of the aniline of part A (0.780 g, 1.55 mmol) intetrahydrofuran (4.0 mL) was added potassium trimethylsilanolate (0.238g, 1.86 mmol). The resulting mixture was stirred at ambient temperaturefor 17 hours, and then additional potassium trimethylsilanolate (0.020g, 0.1955 mmol) was added. After stirring at ambient temperature for 24hours additional potassium trimethylsilanolate (0.040 g, 0.310 mmol) wasadded. After stirring at ambient temperature for 26 hours, the solventwas removed by blowing N₂ over the mixture. To a suspension of theresidue in dichloromethane (10 mL) was added N-methylmorpholine (0.511mL, 4.65 mmol), O-(tetrahydropuranyl)hydroxylamine (0.218 g, 1.86 mmol),followed by PyBroP® (1.08 g, 2.33 mmol). The resulting mixture wasstirred at ambient temperature for 2 days and then concentrated invacuo. The residue was partitioned between H₂O and ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried overNa₂SO₄. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as an off-white solid (0.600 g, 66%).

Part C: To a solution of the protected hydroxamate of part B (0.580 g,0.984 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solutionof 4N HCl in dioxane (2.5 mL, 10.0 mmol). The resulting mixture wasstirred at ambient temperature for 1 hour, then diethyl ether (10 mL)was added. The solids were collected by filtration to give the titlecompound as a white solid (0.437 g, 100%). MS MH⁺ calculated forC₁₉H₂₄O₅N₃S: 406, found 406.

EXAMPLE 393 Preparation ofN-hydroxy-4-[[4-[[4-(trifluoromethoxy)phenyl]amino]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the ester of part C, Example 91 (3.27 g, 7.09mmol) was added Cs₂CO₃ (3.23 g, 9.92 mmol), BINAP (0.066 g, 0.107 mmol),tris(dibenzyldeneacetone)-dipallidium(0) (0.065 g, 0.071 mmol),4-trifluoro-methoxyaniline (1.15 mL, 8.51 mmol) and toluene (14 mL). Theresulting mixture was heated to one hundred degrees Celsius for 22hours. After cooling to ambient temperature, the mixture was filteredthrough a pad of Celite®, washing with ethyl acetate, and the filtratewas concentrated in vacuo. Chromatography (on silica, ethylacetate/hexane) provided the aniline as a tan solid (3.59 g, 91%).

Part B: To a solution of the aniline of part A (1.03 g, 1.84 mmol) intetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.331g, 2.58 mmol). The resulting mixture was stirred at ambient temperaturefor 24 hours, and then additional potassium trimethylsilanolate (0.118g, 0.092 mmol) was added. After stirring at ambient temperature for 24hours, the solvent was removed by blowing N₂ over the mixture. H₂O wasadded and the reaction mixture was acidified (pH 3) with 1N HCl. Theaqueous reaction mixture was extracted with ethyl acetate and thecombined organic layers were washed with saturated NaCl and dried overNa₂SO₄. Concentration in vacuo provided the acid as a tan solid (1.01 g,100%).

Part C: To a suspension of the acid of part B (1.00 g, 1.84 mmol) inN,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.298 g,2.21 mmol), N-methylmorpholine (0.607 mL, 5.52 mmol),O-(tetrahydropuranyl)hydroxylamine (0.323 g, 2.76 mmol) and1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.494 g,2.58 mmol). The resulting mixture was stirred at ambient temperature for17 hours then concentrated in vacuo. The residue was partitioned betweenH₂O and ethyl acetate. The combined organic layers were washed with H₂O,saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄. Chromatography(on silica, ethyl acetate/hexanes) provided the protected hydroxamate asa white solid (0.960 g, 81%).

Part D: To a solution of the protected hydroxamate of part C (0.960 g,1.49 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of4N HCl in dioxane (4.0 mL, 16.0 mmol). The resulting mixture was stirredat ambient temperature for 2.5 hours. The solvent was then removed byblowing N₂ over the reaction mixture. Diethyl ether (20 mL) was addedand the precipitate was collected by filtration to give the titlecompound as a pale pink solid (0.716 g, 100%). MS MH⁺ calculated forC₁₉H₂₁O₅N₃SF₃: 460, found 460.

EXAMPLE 394 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[[4-(trifluoromethoxy)phenyl]amino]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the aniline of part A, Example 392(2.55 g, 4.57mmol) in dioxane (9.0 mL) and methanol (3.0 mL) was added a solution of4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambienttemperature for 2 hours, the reaction mixture was concentrated in vacuoto provide the amine as a tan solid (2.36 g, >100%).

Part B: To a suspension of the amine of part A (1.50 g, 3.03 mmol) inacetonitrile (12 mL) was added K₂CO₃ (1.26 g, 9.09 mmol) and2-bromoethyl methyl ether (0.313 mL, 3.33 mmol). After stirring atreflux for 23 hours, Cs₂CO₃ (2.96 g, 9.09 mmol) was added. After 6 hoursat reflux, the reaction mixture was filtered through a pad of Celite®,washing with dichloromethane. The filtrate was concentrated in vacuo.Chromatography (on silica, methanol/dichloromethane) provided themethoxy ethyl amine as a tan solid (1.13 g, 72%).

Part C: To a solution of the methoxy ethyl amine of part B (1.13 g, 2.19mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanolate(0.561 g, 4.38 mmol). The resulting mixture was stirred at ambienttemperature for 18 hours, and then additional potassiumtrimethylsilanolate (0.140 g, 1.09 mmol) was added. After stirring atambient temperature for 5 hours, the solvent was removed by blowing N₂over the mixture. Water (8 mL) was added and the reaction mixture wasneutralized (pH 7) with 1N HCl. The solids were collected by filtrationand dried by concentration in vacuo with acetonitrile to provide theamino acid as an off-white solid (0.900 g, 82%).

Part D: To a suspension of the amino acid of part C (0.900 g, 1.79 mmol)in N,N-dimethylformamide (8.0 mL) was added 1-hydroxybenzotriazole(0.290 g, 2.15 mmol), N-methylmorpholine (0.590 mL, 5.37 mmol),O-(tetrahydropuranyl)hydroxylamine (0.315 g, 2.69 mmol) and1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.480 g,2.51 mmol). The resulting mixture was stirred at ambient temperature for16 hours then concentrated in vacuo. The residue was partitioned betweenH₂O and ethyl acetate. The combined organic layers were washed with H₂O,saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄. Chromatography(on silica, methanol/dichloromethane) provided the protected hydroxamateas an off-white solid (0.870 g, 81%).

Part E: To a solution of the protected hydroxamate of part D (0.870 g,1.45 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirredat ambient temperature for 2.0 hours. The reaction mixture wasconcentrated in vacuo and then treated again with 4N HCl (3 mL) for 30minutes. The solvent was then removed by blowing N₂ over the reactionmixture. Diethyl ether (30 mL) was added, and the precipitate wascollected by filtration to give the title compound as a pale pink solid(0.771 g, 96%). MS MH⁺ calculated for C₂₂H₂₇O₆N₃SF₃: 518, found 518.

EXAMPLE 395 Preparation ofN-hydroxy-4-[[4-[[4-(trifluoromethyl)phenyl]amino]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the ester of part C, Example 91 (3.16 g, 6.85mmol) was added Cs₂CO₃ (3.13 g, 9.59 mmol), BINAP (0.064 g, 0.103 mmol),tris(dibenzyldeneacetone)-dipallidium(0) (0.063 g, 0.069 mmol),α,α,α-trifluoro-methylaniline (1.03 mL, 8.22 mmol) and toluene (14 mL).The resulting mixture was heated to one hundred degrees Celsius for 17hours. After cooling to ambient temperature, the mixture was filteredthrough a pad of Celite®, washing with dichloromethane, and the filtratewas concentrated in vacuo. Chromatography (on silica, ethylacetate/hexane) provided the aniline as a pale orange foam (3.08 g,83%).

Part B: To a solution of the aniline of part A (1.00 g, 1.84 mmol) intetrahydrofuran (10 mL) was added potassium trimethylsilanolate (0.473g, 3.69 mmol). The resulting mixture was stirred at ambient temperaturefor 25 hours then the solvent was removed by blowing N₂ over themixture. Water was added, and the reaction mixture was acidified (pH 3)with 1N HCl. The aqueous layer was extracted with ethyl acetate and thecombined organic layers were washed with saturated NaCl and dried overNa₂SO₄. Concentration in vacuo provided the acid as an orange foam (1.00g, >100%).

Part C: To a suspension of the acid of part B (0.972 g, 1.84 mmol) inN,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.298 g,2.21 mmol), N-methylmorpholine (0.607 mL, 5.52 mmol),O-(tetrahydropuranyl)hydroxylamine (0.323 g, 2.76 mmol) and1-3-[(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.494 g,2.58 mmol). The resulting mixture was stirred at ambient temperature for18 hours, then concentrated in vacuo. The residue was partitionedbetween H₂O and ethyl acetate. The combined organic layers were washedwith H₂O, saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexanes) provided the protectedhydroxamate as a white solid (0.970 g, 84%).

Part D: To a solution of the protected hydroxamate of part C (0.950 g,1.51 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of4N HCl in dioxane (4.0 mL, 16.0 mmol). The resulting mixture was stirredat ambient temperature for 1.5 hours. Diethyl ether (20 mL) was addedand the precipitate was collected by filtration to give the titlecompound as a white solid (0.630 g, 87%). MS MH⁺ calculated forC₁₉H₂₁O₄N₃SF₃: 444, found 444.

EXAMPLE 396 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[[4-(trifluoromethyl)phenyl]amino]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the aniline of part A, Example 395 (2.07 g,3.82 mmol) in dioxane (9.0 mL) and methanol (3.0 mL) was added asolution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring atambient temperature for 2 hours, the reaction mixture was concentratedin vacuo to provide the amine as a yellow solid (1.89 g, >100%).

Part B: To a suspension of the amine of part A (1.83 g, 3.82 mmol) inacetonitrile (20 mL) was added K₂CO₃ (1.58 g, 11.46 mmol) and2-bromoethyl methyl ether (0.395 mL, 4.20 mmol). After stirring atreflux for 18 hours, the reaction mixture was filtered through a pad ofCelite®, washing with dichloromethane and the filtrate was concentratedin vacuo. Chromatography (on silica, methanol/dichloromethane) providedthe methoxy ethyl amine as an off-white solid (1.58 g, 83%).

Part C: To a solution of the methoxy ethyl amine of part B (1.58 g, 3.15mmol) in tetrahydrofuran (30 mL) was added potassium trimethylsilanolate(0.810 g, 6.31 mmol). The resulting mixture was stirred at ambienttemperature for 3 days, and then the solvent was removed by blowing N₂over the mixture. Water (10 mL) was added and the reaction mixture wasneutralized (pH 7) with 1N HCl. The solids were collected by filtrationand dried by concentration in vacuo with acetonitrile to provide theamino acid as a pink solid (1.32 g, 86%).

Part D: To a suspension of the amino acid of part C (1.32 g, 2.71 mmol)in N,N-dimethylformamide (12 mL) was added 1-hydroxybenzotriazole (0.439g, 3.25 mmol), N-methylmorpholine (0.894 mL, 8.13 mmol),O-(tetrahydropuranyl)hydroxylamine (0.476 g, 4.07 mmol) and1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.727 g,3.79 mmol). The resulting mixture was stirred at ambient temperature for20 hours, then concentrated in vacuo, The residue was partitionedbetween H₂O and ethyl acetate. The combined organic layers were washedwith H₂O, saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, methanol/ethyl acetate) provided theprotected hydroxamate as an off-white solid (1.39 g, 88%).

Part E: To a solution of the protected hydroxamate of part D (1.40 g,2.39 mmol) in dioxane (3 mL) and methanol (1 mL) was added a solution of4N HCl in dioxane (5.98 mL, 23.9 mmol). The resulting mixture wasstirred at ambient temperature for 2.5 hours. The reaction mixture wasconcentrated almost to dryness, by blowing N₂ over the reaction mixture.Diethyl ether (25 mL) was added and the precipitate was collected byfiltration. The resulting solid was dissolved in methanol (1 mL) andtreated with 4N HCl in dioxane (1.5 mL). After stirring at ambienttemperature for 1.5 hours, the reaction mixture was slowly added todiethyl ether (50 mL). The resulting precipitate was collected byfiltration to give the title compound as an off-white solid (1.08 g,84%). MS MH⁺ calculated for C₂₂H₂₇O₅N₃SF₃: 502, found 502.

EXAMPLE 397 Preparation of ethyl1-(2-methoxyethyl)-3-phenylpropoxy)phenyl]sulfonyl]-4-piperidinecarboxylate

Part A: A mixture of the methoxyethyl amine,ethyl-4-[[4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(1.5 g, 4.0 mmol), 3-phenyl-1-propanol (2.2 mL, 16 mmol), and K₂CO₃ (2.2g, 16 mmol) in DMAC (6 mL) was heated at 125 degrees Celsius for 1 dayand at 135 degrees Celsius for 3 days. After the mixture wasconcentrated in vacuo, diluted with water, and extracted with ethylacetate. The organic layer was washed with water and brine, dried overmagnesium sulfate, and concentrated in vacuo to give a crude oil. Theoil was purified by flash chromatography (20:80 hexane/ethyl acetate) toafford the ether as a brown oil (1.35 g, 67%).

Part B: A mixture of the ether of part A 1.3 g, 2.7 mmol) and a 50 NaOHaqueous solution (2.1 g, 27 mmol) in THF (23 mL), EtOH (23 mL), and H₂O(12 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for24 hours. The material was concentrated in vacuo and triturated withdiethyl ether to give a solid. The solid was dissolved in water, cooledwith an ice bath, acidified with concentrated hydrochloric acid. Theprecipitate was isolated by filtration, washed with cold water, anddried at ambient temperature in a vacuum oven for 3 days to afford thecrude acid.

A mixture of the above crude acid (1.1 g), N-hydroxybenzotriazole (0.36g, 2.7 mmol), 4-methylmorpholine (0.74 mL, 6.7 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.39 g, 3.3 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.60 g, 3.1mmol) in DMF (11 mL) was stirred at ambient temperature under a nitrogenatmosphere for 18 hours. The mixture was concentrated in vacuo, anddissolved into a solution of saturated NaHCO₃ (90 mL), ethyl acetate (25mL,), and a few drops of 2N NaOH. The aqueous layer was extracted withadditional ethyl acetate. The combined ethyl acetate layers were washedwith saturated NaHCO₃ solution, water, and brine. After drying overmagnesium sulfate, the filtrate was concentrated in vacuo to give a darkyellow oil. The oil was purified by flash chromatography (40:60acetonitrile/toluene) to afford the protected hydroxamate as a yellowoil (0.32 g, 25%): MS MH+ calcd. for C₂₉H₄₀N₂O₇S 561, found 561.

Part C: To a solution of the protected hydroxamate of part 2B (0.28 g,0.50 mmol) in methanol (4.0 mL) was added acetyl chloride (0.11 mL, 1.5mmol) and the solution was stirred at ambient temperature under anitrogen atmosphere for 2.5 hours. The solution was diluted with diethylether and concentrated. The solid was triturated with diethyl ether anddried at 40 degrees Celsius in a vacuum oven to give the title compoundas an off white solid (0.15 g, 20%): MS MH+ calcd. for C₂₄H₃₂N₂O₆S 477,found 477.

EXAMPLE 398 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxyethoxy)phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, part E (14.36 g, 40mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), aportion (about 2 g) of 4-Angstrom molecular sieves,(1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodiumcyanoborohydride (7.05 g, 112 mmol). The solution was heated at refluxfor 8 hours. The precipitated solids were removed by filtration and thefiltrate was concentrated in vacuo. The residue was diluted with H₂O(400 mL) and extracted with ethyl acetate. The organic layer was washedwith saturated NaCl and dried over MgSO₄, filtered and concentrated invacuo. The solid was filtered, washed with H₂O/diethyl ether to give thedesired cyclopropyl amine{ethyl-4-[[4-fluorophenylsulfonyl)]-1-cyclopropyl-4-piperidinecarboxylate}as a white solid (11.83 g, 81.5%). MS MH⁺ calculated for C₁₇H₂₂NO₄SF:356, found: 356.

Part B: A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol),ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate(7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135 degrees Celsius for18 hours under an atmosphere of nitrogen. The mixture was concentratedin vacuo, diluted with water, and extracted with ethyl acetate. Thecombined ethyl acetate layers were washed with water and brine, driedover magnesium sulfate, concentrated in vacuo, dissolved in diethylether, precipitated as the hydrochloride salt, and dried at 40 degreesCelsius in a vacuum oven. The solid was dissolved into a mixture ofwater, acetonitrile, and ethanol and then the pH was adjusted to 12 with1N NaOH solution. The mixture was concentrated in vacuo to removeethanol and acetonitrile. The solid was isolated by filtration, washedwith water, and dried at 50 degrees Celsius in a vacuum oven to affordthe ether as a white solid (1.8 g, 68%): MS+ calcd. for C₂₅H₃₁NO₆S 474,found 474. Anal. calcd. for C₂₅H₃₁NO₆S: C, 63.40; H, 6.60; N, 2.96; S,6.77. Found: C, 63.35; H, 6.59; N, 2.99; S, 6.61.

Part C: A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50%NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), andH₂O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmospherefor 24 hours. The material was concentrated in vacuo and triturated withdiethyl ether to give a solid. The tan solid was dissolved into amixture of water, ethanol, and THF, precipitated by adjusting the pH to3 with concentrated hydrochloric acid, concentrated in vacuo, trituratedwith water, and dried at 50 degrees Celsius in a vacuum oven to give acrude white solid acid (2.3 g).

A mixture of the crude white solid acid (2.3 g), N-hydroxybenzotriazole(1.9 g, 14 mmol), 4-methylmorpholine (1.6 mL, 14 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.1 g, 9.4 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14mmol) in DMF (90 mL) was stirred at ambient temperature under a nitrogenatmosphere for 2 days. The mixture was concentrated in vacuo, dilutedwith water, and extracted with ethyl acetate. The organic layer waswashed with 1N NaOH solution, water, and brine, dried over magnesiumsulfate, concentrated in vacuo, and purification by flash chromatography(20:80 to 40:60 ethyl acetate/toluene) to afford the protectedhydroxamate as a white solid: (0.43 g, 21%): MS MH+ calcd. forC₂₈H₃₆N₂O₇S 545, found 545. Anal. calcd. for C₂₈H₃₆N₂O₇S: C, 61.74; H,6.66; N, 5.14; S, 5.89. Found: C, 61.72; H, 6.75; N, 5.06; S, 5.91.

Additional compound was isolated by acidifying the aqueous layer to pHof 3, collecting the solid by filtration, and drying to give a whitesolid (0.80 g).

Part D: To an ambient temperature solution of acetyl chloride (0.31 mL,4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added theprotected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for2.5 hours, the precipitate was collected by filtration, washed withdiethyl ether, and dried at 45 degrees Celsius in a vacuum oven toafford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd.for C₂₃H₂₈N₂O₆S 461, found 461. Anal. calcd. for C₂₃H₂₈N₂O₆S.1.5HCl: C,53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S,6.16.

EXAMPLE 399 Preparation ofhydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

Part A: A solution of the amine hydrochloride salt of the product ofExample 410(2.4 g, 4.6 mmol), 3-picolyl chloride (1.5 g, 8.8 mmol), andpotassium carbonate (4.3 g, 31 mmol) in DMF (12) was heated at 50degrees Celsius for 1 day under an atmosphere of nitrogen. The mixturewas concentrated in vacuo, dissolved into water, and extracted withethyl acetate. The organic layers were washed with water and brine,dried over magnesium sulfate, concentrated in vacuo. The residue waspurified by flash chromatography (50:50 ethyl acetate/hexane) to affordthe 3-picolyl amine as an amber oil (1.6 g, 60%): MS MH+ calcd. forC₂₇H₂₇N₂O₆SF₃ 565, found 565. Anal. calcd. for C₂₇H₂₇N₂O₆SF₃: C, 57.44;H, 4.82; N, 4.96; S, 5.68. Found: C, 57.49; H, 5.10; N, 4.69; S, 5.67.

Part B: A mixture of the 3-picolyl amine of part 4A (1.5 g, 2.6 mmol)and a 50% NaOH aqueous solution (2.1 g, 26 mmol) in THF (22 mL), EtOH(22 mL), and H₂O (11 mL) was heated at 65 degrees Celsius under anitrogen atmosphere for 24 hours. The material was concentrated in vacuoand triturated with diethyl ether to give a solid. The tan solid wasdissolved into water and the pH was adjusted to 1 with concentratedhydrochloric acid. The mixture was concentrated in vacuo, and dried in a45 degrees Celsius vacuum oven to afford the crude white solid acid (2.5g): MS MH+ calcd. for C₂₅H₂₃N₂O₆SF₃ 537, found 537.

Part C: A mixture of the crude white acid of part B (2.5 g),N-hydroxybenzotriazole (1.0 g, 7.7 mmol), 4-methylmorpholine (0.64 mL,7.7 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.60 g, 5.1 mmol),and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g,7.7 mmol) in DMF (40 mL) was stirred at ambient temperature under anitrogen atmosphere for 5 days. The mixture was concentrated in vacuo,diluted with ethyl acetate, and washed with water and brine. The organiclayer was dried over magnesium sulfate, concentrated in vacuo, andpurified by flash chromatography (5:95 methanol/chloroform) to affordthe protected hydroxamate as a white foam (1.1 g, 66%): MS MH+ calcd.for C₃₀H₃₂N₃O₇SF₃ 636, found 636.

Part D: An ambient temperature solution of the protected hydroxamate ofpart C (1.0 g, 1.6 mmol) and acetyl chloride (0.34 mL, 4.7 mmol) inmethanol (11 mL) under a nitrogen atmosphere was stirring for 2.5 hours,and then poured into diethyl ether. The solid was isolated by filtrationand dried at 46 degrees Celsius in a vacuum oven to afford the titlecompound as a white solid (0.85 g, 87%): Anal. calcd. forC₂₅H₂₄N₃O₆SF₃.2.2HCl: C, 47.53; H, 4.18; N, 6.65; S, 5.08. Found: C,47.27; H, 4.34; N, 6.60; S, 5.29. MS MH+ calcd. for C₂₅H₂₄N₃O₆SF₃ 552,found 552.

EXAMPLE 400 Preparation ofN-Hydroxy-4-[4-(4-methoxyphenoxy)phenyl]sulfonyl]-1-(2-pyridinylmethyl)-4-piperidinecarboxamide,dihydrochloride

Part A: Ethyl-4-[[4-fluorophenylsulfonyl)]-4-piperidinecarboxylatehydrochloride (2.02 g, 5.76 mmol) was combined with powdered potassiumcarbonate (2.48 g, 18 mmol) and N,N-dimethylformamide (12 mL). 2-Picolylhydrochloride (1.0 g, 6.1 mmol) was added, and the mixture was stirredfor twenty-four hours at forty degrees Celsius. The reaction mixture wasdiluted with water (80 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were dried over magnesium sulfate,concentrated, and subjected to chromatography (ethyl acetate) affordingthe desired pyridine ester as an oil (2.30 g, quantitative).

Part B: The pyridine ethyl ester from Part A (2.30 g, 5.76 mmol) wascombined with powdered potassium carbonate (1.29 g, 9 mmol),4-methoxyphenol (1.12 g, 9.0 mmol), and N,N-dimethylformamide (3 mL),and the mixture was heated at seventy five to eighty degrees C. fortwenty-four hours. Additional 4-methoxyphenol (300 mg) and potassiumcarbonate (350 mg) were added, and the mixture was stirred an additionalthree hours at ninety degrees Celsius. The mixture was diluted withwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried using magnesium sulfate, concentrated, andchromatographed, affording the desired ester as an oil (2.85 g,quantitative).

Part C: The ester of part B (2.85 g) was combined with ethanol (18 mL),water (6 mL), and potassium hydroxide (2.24 g, 40 mmol). The mixture wasbrought to reflux and heated for four and one-half hours. It was cooledto zero degrees Celsius and acidified using concentrated aqueoushydrogen chloride. The solvent was removed, and the resulting solidswere dried by azeolroping with acetonitrile, vacuum was applied untilconstant weight was achieved.

The crude acid hydrochloride was stirred with N-methylmorpholine (1 mL),1-hydroxybenzotriazole (0.945 g, 7 mmol), O-tetrahydropyranylhydroxylamine (0.82 g, 7 mmol), and N,N-dimethyformamide (21 mL). Afterten minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.34 g, 7 mmol) was added, and the mixture was stirred overnight. Thereaction was then diluted with half-saturated aqueous sodium bicarbonate(100 mL), and extracted with ethyl acetate (200 mL, then 50 mL). Thecombined organic layers were dried over magnesium sulfate, concentrated,and chromatographed (9:1 ethyl acetate: hexane) to afford the desiredO-tetrahydropyranyl-protected hydroxamate as a yellow oil (2.82 g, 88%).

Part D: The O-tetrahydropyranyl-protected hydroxamate of part C (2.82 g,5 mmol) was diluted with methanol (20 mL). Acetyl chloride (2.1 mL, 30mmol) was added over two minutes. The reaction was stirred for 4 hoursat ambient temperature, then concentrated to afford 2.59 g of crudedihydrochloride salt, which was recrystallized from ethanol/water,affording 525 mg (18%) of the title hydroxamate in the first crop. MS(EI) MH⁺ calculated for C₂₅H₂₇N₃O₆S: 498, found 498.

EXAMPLE 401 Preparation ofN-Hydroxy-4-[4-(4-cyclohexylthio)phenyl]sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxamide,hydrochloride

Part A:Ethyl-4-[[4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(5.5 g, 14 mmol) was combined with powdered potassium carbonate (2.76 g, 20 mmol), N,N-dimethylformamide (7 mL), and cyclohexyl mercaptan (2.4mL, 20 mmol) and was stirred at ambient temperature for two days. Thetemperature was raised to forty-five to fifty degrees Celsius andstirring was continued another 24 hours. Additional quantities ofpotassium carbonate (1.0 g) and cyclohexyl mercaptan (1.0 mL) wereintroduced and the reaction was heated sixteen additional hours. Themixture was diluted with water (50 mL), and extracted with ethyl acetate(100 mL, then 25 mL). The combined organic layers were dried,concentrated, and chromatographed (ethyl acetate) affording the desiredsulfide as a yellow oil (3.59 mL, 53%).

Part B: The sulfide from Part A (3.59 gm, 7.4 mmol) was converted totetrahydropyranyl-protected hydroxamate by saponification followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride coupling bythe method of Example 401, part C, affording 2.16 g (54%) of the desiredtetrahydropyranyl-protected hydroxamate as an oil.

Part C: The tetrahydropyranyl-protected hydroxamate from part B (2.16 g,4 mmol) was diluted with methanol (16 mL). Acetyl chloride (1.1 mL, 16mmol) was added over one minute. The reaction was stirred for fourhours, then concentrated and azeotroped with acetonitrile to afford 1.11g of crude product, which was recrystallized from absolute ethanol toafford in the first crop 804 mg of the title compound (41%). MS (EI) MH⁺calculated for C₂₁H₃₂N₂O₅S₂: 457, found 457.

EXAMPLE 402 Preparation ofN-Hydroxyl-1-(2-methoxyethyl)-4-[[(phenylmethoxy)phenyl]-sulfonyl]-4-piperidinecarboxamide

Part A:Ethyl-4-[(4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(1.58 g, 4.5 mmol) was combined with powdered potassium carbonate (2.42g , 18 mmol), N,N-dimethylacetamide (5 mL), and benzyl alcohol (1.94 mL,18 mmol) and was stirred at one hundred forty degrees Celsius forsixteen hours. The mixture was diluted with water (50 mL), and extractedwith ethyl acetate (125 mL, then 25 mL). The combined organic layerswere dried, concentrated, and chromatographed (ethyl acetate) affordingthe desired ethyl ester as an oil (1.16 mL, 56%).

Part B : The ethyl ester from part A (1.16 gm, 2.5 mmol) was convertedto the tetrahydropyranyl-protected hydroxamate by saponificationfollowed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloridecoupling by the method of Example 401, part C, affording 880 mg (80%) ofthe tetrahydropyranyl-protected hydroxamate as an oil.

Part C: The tetrahydropyranyl-protected hydroxamate from Part B (880 mg,2.0 mmol) was diluted with methanol (8 mL). Acetyl chloride (0.68 mL, 10mmol) was added over one minute. The reaction was stirred for threehours, then concentrated and azeotroped with acetonitrile to afford thecrude product, which was converted to free base by adding enoughsaturated aqueous sodium bicarbonate (25 mL) to neutralize the hydrogenchloride, then extracting with ethyl acetate (100 mL, then 50 mL). Theorganic phase was dried with magnesium sulfate, concentrated, andchromatographed (9:1 dichloromethane:methanol, 1% ammonium hydroxide),affording the title hydroxamate as a glass, (327 mg, 36%). MS (EI) MH⁺calculated for C₂₂H₂₈N₂O₆S: 447, found 447.

EXAMPLE 403 Preparation ofN-hydroxyl-1-(1-methylethyl)-4-[[4-(2-phenylethoxy)phenyl]sulfonyl]-4-piperidinecarboxamide

Part A:Ethyl-4-[[4-fluorophenylsulfonyl)]-1-(1-methylethyl)-4-piperidinecarboxylate(2.75 g, 7.7 mmol) was combined with powdered potassium carbonate (2.62g , 19 mmol), N,N-dimethylformamide (10 mL), and 2-phenylethanol (2.0mL, 19 mmol) and was stirred at eighty-five degrees Celsius for twentyfour hours. Additional potassium carbonate (1.3 g) and 2-phenylethanolwere added, and the temperature was raised to one hundred-ten degreesCelsius for forty-eight hours, then one hundred thirty-five degreesCelsius for four hours. The mixture was diluted with water (100 mL), andextracted with ethyl acetate (200 mL, then 25 mL). The combined organiclayers were dried, concentrated, and chromatographed (ethyl acetate)affording the desired ethyl ester as an oil (3.19 mL, 90%).

Part B: The ethyl ester from Part A (3.19 gm, 6.9 mmol) was converted totetrahydropyranyl-protected hydroxamate by saponification followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride coupling bythe method of Example 401, part C, affording 2.27 g (64%) of the titlecompound as an oil.

Part C: The tetrahydropyranyl-protected hydroxamate from Part B (2.27mg, 4.4 mmol) was diluted with methanol (16 mL). Acetyl chloride (0.68mL, 10 mmol) was added over one minute. The reaction was stirred forthree hours, then concentrated and azeotroped with acetonitrile toafford the crude product, which was converted to free base by addingenough saturated sodium bicarbonate (25 mL) to neutralize the hydrogenchloride, then extracting with ethyl acetate (100, then 50 mL). Theorganic phase was dried with magnesium sulfate, concentrated, andchromatographed (9:1 dichloromethane:methanol, 1% ammonium hydroxide),affording the desired hydroxamate as a glass, (819 mg, 42%). MS (EI) MH⁺calculated for C₂₃H₃₀N₂O₅S: 449, found 449.

EXAMPLE 404 Preparation ofN-hydroxy-4-[(4-phenylthiophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,phosphoric acid salt

N-Hydroxy-4-[[4-phenylthiophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide(430 mg, 1.0 mmol) was dissolved in methanol (15 mL). Concentratedphosphoric acid (67 μL) was added, and the solution was thenconcentrated in vacuo. The residue was recrystallized from methanol,isolated by filtration, and then recrystallized a second time frommethanol/methyl t-butyl ether affording the title phosphate as a solid(215 mg, 41%). Analytical calculation for C₂₁H₂₂N₂O₄.H₃PO₄: C, 47.72; H,4.77; N, 5.30, found: C, 47.63; H, 5.04; N, 4.82.

EXAMPLE 405 Preparation ofN-hydroxy-4-[(4-phenylthiophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,p-tolueneaulfonic acid salt

N-Hydroxy-4-[[4-phenylthiophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide(516 mg, 1.0 mmol) was combined with p-toluenesulfonic acid, monohydrate(200 mg, 1.05 mmol), and the mixture was dissolved in methanol (3 mL).After four hours, the resulting white precipitate was collected byfiltration affording 488 mg (81%) of the title tosylate salt, which wascharacterized spectroscopically.

EXAMPLE 406 Preparation of4-[[4-[(2,3-dihydro-1H-inden-2-yl)amino]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: A solution of the product of Example 9, Part D (0.979 g, 2.36mmol), 2-aminoindan hydrochloride (1.00 g, 5.89 mmol), and cesiumcarbonate (1.92 g, 5.89 mmol) in N,N-dimethylformamide (8 mL) was heatedto 95 degrees Celsius for 22 hours. The reaction was then cooled,diluted with ethyl acetate (50 mL), and washed with three times withwater and once with brine, then dried over sodium sulfate. Concentrationgave a residue that was chromatographed on silica gel. Elution withethyl acetate/hexane (30/70) afforded the desired 4-aminosulfonederivative (450 mg, 36%). MS (EI) MH⁺ calculated for C₂₈H₃₆N₂O₆S: 529,found 529. HRMS M+ calculated for C₂₈H₃₆N₂O₆S: 528.2294, found 528.2306.

Part B: To a solution of the ethyl ester of part A (450 mg, 0.85 mmol)in ethanol (3 mL), water (2 mL) and tetrahydrofuran (3 mL) was addedsodium hydroxide (340 mg, 8.5 mmol), and the solution was heated to 60degrees Celsius for 26 hours. The solution was cooled and then dilutedwith water (10 mL) followed by 10% aqueous hydrochloric acid (3 mL) tobring the pH to 2. The resulting solution was extracted with ethylacetate. The organic extracts were combined and washed with water andbrine and dried over sodium sulfate to afford the desired carboxylicacid as a pale brown foam (376 mg, 88%). Analytical calculation forC₂₆H₃₂N₂O₆S: C, 62.38; H, 6.44; N, 5.60; S, 6.40. Found: C, 62.48; H,6.69; N, 5.42; S, 6.27.

Part C: To a solution of the carboxylic acid of part B (305 mg, 0.609mmol) in N,N-dimethylformamide (2 mL) was added 4-methylmorpholine (247mg, 2.44 mmol), N-hydroxybenzotriazole (99 mg, 0.73 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (152 mg,0.79 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (97 mg,0.82 mmol). After stirring for 2 days at ambient temperature, thesolution was concentrated to an oil. Water was added and the mixture wasextracted with ethyl acetate. The organic extracts were washed withwater and brine and dried over sodium sulfate. Concentration gave abrown foam that was chromatographed on silica gel. Elution with ethylacetate/hexane (40/60) afforded the protected hydroxamate derivative asa colorless glass (0.38 g, 100%). MS MH⁺ calculated for C₃₁H₄₁N₃O₇S:600, found 600.

Part D: To a solution of the protected hydroxamate of part C (350 mg,0.584 mmol) in methanol (3 mL) and 1,4-dioxane (1.5 mL) was added 4 NHCl/1,4-dioxane (1.5 mL, 6 mmol), and the solution was stirred atambient temperature for 3 hours. Concentration gave a residue that wastriturated with diethyl ether to afford the title compound as a solid,which was filtered and dried for 40 hours at 51 degrees Celsius (249 mg,94%). HRMS (ESI) MH⁺ calculated for C₂₁H₂₅N₃O₄S: 416.1644, found416.1647.

EXAMPLE 407 Preparation of4-[[4-(dimethylamino)phenyl]sulfonyl]-N-hydroxy-4-piperidine-carboxamide,monohydrochloride

Part A: A solution of the product of Example 9, Part D (0.979 g, 2.36mmol), 2-aminoindan hydrochloride (1.00 g, 5.89 mmol), and cesiumcarbonate (1.92 g, 5.89 mmol) in N,N-dimethylformamide (8 mL) was heatedto 95 degrees Celsius for 22 hours. The reaction was then cooled,diluted with ethyl acetate (50 mL), and washed with three times withwater and once with brine, then dried over sodium sulfate. Concentrationgave a residue that was chromatographed on silica gel. Elution withethyl acetace/hexane (30/70) afforded the 4-N,N-dimethylaminosulfonederivative (590 mg, 57%) alongside the product of example 406. MS (EI)MH⁺ calculated for C₂₁H₃₂N₂O₆S: 441, found 441. HRMS calculated forC₂₁H₃₂N₂O₆S: 440.1981, found 440.1978.

Part B: To a solution of the ethyl ester of part A (580 mg, 1.3 mmol) inethanol (4 mL), water (3 mL) and tetrahydrofuran (4 mL) was added sodiumhydroxide (520 mg, 13 mmol), and the solution was heated to 62 degreesCelsius for 5 hours. The solution was cooled and then diluted with water(5 mL) followed by 10% aqueous hydrochloric acid (5 mL) to acidify topH=2. The resulting solution was extracted with ethyl acetate. Theorganic extracts were combined and washed with water and brine and driedover sodium sulfate to afford the desired carboxylic acid as a palebrown foam (520 mg, 97%). MS MH⁺ calculated for C₁₉H₂₈N₂O₆S: 413, found413.

Part C: To a solution of the carboxylic acid of part B (500 mg, 1.21mmol) in N,N-dimethylformamide (4 mL) was added 4-methylmorpholine (490mg, 4.8 mmol), N-hydroxybenzotriazole (197 mg, 1.45 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (302 mg,1.57 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (192mg, 1.63 mmol). After stirring for 2 days at ambient temperature, thesolution was concentrated to an oil. Water (25 mL) was added and themixture was extracted with ethyl acetate. The organic extracts werewashed with water and brine and dried over sodium sulfate. Concentrationgave a brown oil, which crystallized from a mixture of ethyl acetate,hexane and methylene chloride (1:1:2) to afford the protectedhydroxamate derivative as a colorless solid (506 mg, 82%). MS MH⁺calculated for C₂₄H₃₇N₃O₇S: 512, found 512.

Part D: To a solution of the protected hydroxamate of part C (477 mg,0.932 mmol) in methanol (3 mL) and 1,4-dioxane (3 mL) was added 4 NHCl/1,4-dioxane (2.3 mL, 9.3 mmol), and the solution was stirred atambient temperature for 3 hours. Concentration gave a residue that wastriturated with diethyl ether to afford the title compound as a solid,which was filtered and dried for 40 hours at 51 degrees Celsius (372 mg,100%). HRMS (ESI) MH⁺ calculated for C₁₄H₂₁N₃O₄S: 328.1331, found328.1343.

EXAMPLE 408 Preparation of1-cyclopropyl-4-[[4-[(2,3-dihydro-1,4-benzodioxin-6-yl)oxy]phenyl]-sulfonyl]-N-hydroxy-4-piperidine-carboxamide,monohydrochloride

Part A: To a solution of the product of Example 398, Part A (1.36 g,3.47 mol) in N,N-dimethylformamide (8 mL) was added6-hydroxybenzo-1,4-dioxane (792 mg, 5.21 mmol) followed by cesiumcarbonate (2.83 g, 8.69 mmol) and the solution was heated at one hundreddegrees Celsius for 20 hours. The solution was partitioned between ethylacetate and H₂O. The aqueous layer was extracted with ethyl acetate andthe combined organic layers were washed with H₂O and saturated NaCl anddried over Na₂SO₄. Filtration through a silica pad (ethylacetate/hexane) provided the phenoxyphenyl compound as an orange oil(1.61 g, quantitative yield). MS (CI) MH⁺ calculated for C₂₅H₂₉O₇S: 488,found 488.

Part B: To a solution of the phenoxyphenol compound of part A (1.81 g,<3.47 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was addedsodium hydroxide (1.39 g, 34.7 mmol) in H₂O (5 mL). The solution washeated to sixty degrees Celsius for 20 hours. The solution wasconcentrated in vacuo and the aqueous residue was acidified to pH 2 with10% HCl. The resulting solid was collected by vacuum filtration toprovide the acid as a yellow solid (1.23 g, 72%). MS (CI) MH⁺ calculatedfor C₂₃H₂₅NO₇S: 460, found 460. HRMS calculated for C₂₃H₂₅NO₇S:460.1430, found 460.1445.

Part C: To a suspension of the acid of part B (1.21 g, 2.46 mmol) inN,N-dimethylformamide (20 mL) was added N-hydroxybenzotriazole (399 mg,2.95 mmol), 4-methylmorpholine (0.81 mL, 7.38 mmol) andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (432 mg, 3.69 mmol). Afterstirring for one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (660 mg, 3.44 mmol) was added and the solution was stirredfor 20 hours at ambient temperature. The solution was partitionedbetween ethyl acetate and H₂O and the aqueous layer was extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane)provided the protected hydroxamate as a yellow oil (940 mg, 70%). MS(CI) MH⁺ calculated for C₂₈H₃₄N₂O₂S: 559, found 559.

Part D: To a solution of the protected hydroxamate of part C (920 mg,1.68 mmol) in 1,4-dioxane (15 mL) was added 4N HCl in 1,4-dioxane (10mL). After stirring at ambient temperature for 2 hours the resultingprecipitate was collected by vacuum filtration and washed with ethylether to provided the title compound as a white solid (510 mg, 60%). MS(CI) MH⁺ calculated for C₂₃H₂₆N₂OS: 475, found 475. HRMS calculated forC₂₃H₂₆NO₇S: 475.1539, found 475.1553. Analytical calculation forC₂₃H₂₆N₂O₇S.1.15HCl.0.5H₂O: C, 52.57; H, 5.40; N, 5.33; Cl, 7.76. Found:C, 52.62; H, 5.42; N, 5.79; Cl, 7.71.

EXAMPLE 409 Preparation ofN-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94g, 9.03 mmol) and α,α,α-trifluoro-p-cresol (877 mg, 5.41 mmol). Thesolution was heated to ninety degrees Celsius for 20 hours. The solutionwas partitioned between ethyl acetate and H₂O and the organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Filtration through asilica pad (ethyl acetate) provided the diaryl ether as a yellow oil(2.30 g, quantitative yield). MS (CI) MH⁺ calculated for C₂₆H₃₀N₇SF₃:558, found 558.

Part B: To a solution of the diaryl ether of part A (2.30 g, <3.61 mmol)in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodiumhydroxide (1.44 g, 36.1 mmol) in H₂O (5 mL) and the solution was heatedto sixty degrees Celsius for 18 hours. The solution was concentrated andthe aqueous residue was acidified to pH=2 with 10% HCl and extractedwith ethyl acetate. The organic layer was washed with saturated NaCl anddried over Na₂SO₄. Concentration in vacuo provided the acid as a solid(2.11 g, quantitative yield). MS (CI) MH⁺ calculated for C₂₄H₂₆NO₇SF₃:530, found 530.

Part C: To a solution of the acid of part B (2.11 g, <3.61 mmol) inN,N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (586 mg,4.33 mmol), 4-methylmorpholine (1.19 mL, 10.83 mmol) andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (634 mg, 5.41 mmol). Afterstirring for one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (969 mg, 5.05 mmol) was added and the solution was stirredfor 18 hours. The solution was partitioned between ethyl acetate andH₂O. The aqueous layer was extracted with ethyl acetate and the combinedorganic layers were washed with H₂O and saturated NaCl and dried overMgSO₄. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as a clear, colorless oil (1.40 g, 62%) MS (CI)MH⁺ calculated for C₂₉H₃₅N₂O₈SF₃: 629, found 629.

Part D: To a solution of the protected hydroxamate of part C (1.40 g,2.23 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in 1,4-dioxane (15mL) and the solution was stirred for 2 hours. The solution was dilutedwith ethyl ether and the resulting precipitate was collected by vacuumfiltration to provide the title compound as a white solid (747 mg, 70%).HPLC purity: 97.5%. MS (CI) MH⁺ calculated for C₁₉H₁₉N₂O₅SF₃: 445, found445. HRMS calculated for C₁₉H₁₉N₂O₅SF₃: 445.1045, found 445.1052.Analytical calculation for C₁₉H₁₉N₂O₅SF₃.0.5H₂O.1.0HCl: C, 46.58; H,4.32; N, 5.72; S, 6.55; Cl, 7.24. Found: C, 46.58; H, 3.82; N, 5.61; S,6.96; Cl, 7.37.

EXAMPLE 410 Preparation ofN-hydroxy-4-[[4-[(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94g, 9.03 mmol) and 4-(trifluoromethoxy)phenol (0.70 mL, 5.41 mmol). Thesolution was heated to ninety degrees Celsius for 20 hours. The solutionwas partitioned between ethyl acetate and H₂O and the organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Filtration through asilica pad (ethyl acetate) provided the phenoxyphenol as a yellow oil(2.11 g, quantitative yield). MS (CI) MNa⁺ calculated for C₂₆H₃₀NO₈SF₃:596, found 596.

Part B: To a solution of the phenoxyphenol of part A (2.11 g, <3.61mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodiumhydroxide (1.44 g, 36.1 mmol) in H₂O (5 mL), and the solution was heatedto sixty degrees Celsius for 18 hours. The solution was concentrated andthe aqueous residue was acidified to pH=2 with 10% HCl and extractedwith ethyl acetate. The organic layer was washed with saturated NaCl anddried over Na₂SO₄. Concentration in vacuo provided the acid as a solid(2.2 g, quantitative yield). MS (CI) MH⁺ calculated for C₂₄H₂₆NO₈SF₃:546, found 546.

Part C: To a solution of the acid of part B (2.2 g) inN,N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (586 mg,4.33 mmol), 4-methylmorpholine (1.19 mL, 10.83 mmol) andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (634 mg, 5.41 mmol). Afterstirring for thirty minutes,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (969 mg,5.05 mmol) was added and the solution was stirred for 96 hours. Thesolution was partitioned between ethyl acetate and H₂O. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere washed with H₂O and saturated NaCl and dried over MgSO₄.Chromatography (on silica, ethyl acetate/hexane) provided the protectedhydroxamate as a clear, colorless oil (1.26 g, 53%)

Part D: To a solution of the protected hydroxamate of part C (1.26 g,1.96 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in 1,4-dioxane (10mL) and the solution was stirred for 2 hours. The solution was dilutedwith ethyl ether and the resulting precipitate was collected by vacuumfiltration to provide the title compound as a white solid (455 mg, 47%).HPLC purity: 98%. MS (CI) MH⁺ calculated for C₁₉H₁₉N₂O₆SF₃: 461, found461. HRMS calculated for C₁₉H₁₉N₂O₆SF₃: 461.0994, found 461.0997.Analytical calculation for C₁₉H₁₉N₂O₆SF₃.1.0HCl: C, 45.93; H, 4.06; N,5.64; S, 6.45; Cl, 6.45. Found: C, 46.23; H, 4.07; N, 5.66; S, 6.59; Cl,7.03.

EXAMPLE 411 Preparation of1-cyclopropyl-4-[[4-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-phenyl]sulfonyl]-N-hydroxy-4-piperidine-carboxamide,monohydrochloride

Part A: To a solution of ester of part C, Example 91 (1.57 g, 3.40 mmol)in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL). Afterstirring for one hour the resulting precipitate was collected by vacuumfiltration to provide the amine hydrochloride salt as a white solid(1.16 g, 86%).

Part B: To a slurry of the amine hydrochloride salt of part A (1.16 g,2.91 mmol) in methanol (10 mL) was added acetic acid (1.68 mL, 29.1mmol) followed by (1-ethyoxycyclopropyl)oxytrimethylsilane (3.51 mL,17.5 mmol) and sodium cyanoborohydride (823 mg, 13.1 mmol). The solutionwas heated to reflux for six hours. The solution was filtered and thefiltrate was concentrated in vacuo. The residue was dissolved into ethylacetate and washed with H₂O, aqueous sodium hydroxide and saturated NaCland dried over MgSO₄. Concentration in vacuo provided the N-cyclopropylcompound as a white solid (1.03 g, 88%).

Part C: To a solution of the N-cyclopropyl compound of part B (1.0 g,2.49 mmol) in toluene (6 mL) was added cesium carbonate (1.14 g, 3.49mmol), tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.075 mmol)R-(+)-2,21-bis(diphenylphosphino)-1,1′-binaphthyl (69 mg, 0.112 mmol)and 1,4-benzodioxane-6-amine (451 mg, 2.99 mmol) and the solution washeated to one hundred degrees Celsius for 19 hours. The solution wasdiluted with ethyl ether and filtered through Super Cel®. The filtratewas concentrated and chromatography (on silica, ethyl acetate/hexane)provided the aniline compound as an orange oil (561 mg, 48%). MS (CI)MH⁺ calculated for C₂₄H₂₈N₂O₆S: 473, found 473.

Part D: To a solution of the aniline compound of part C (550 mg, 1.16mmol) in tetrahydrofuran (10 mL) was added potassium trimethylsilanolate(297 mg, 3.48 mmol) and the solution was stirred for 18 hours at ambienttemperature. The solution was concentrated and the resulting residue wassuspended in H₂O. The solid was collected by vacuum filtration toprovide the crude acid (282 mg).

Part E: To a solution of the crude acid of part D (282 mg, 0.62 mmol) inN,N-dimethylformamide (10 mL) was added N-hydroxybenzotriazole (100 mg,0.74 mmol), 4-methylmorpholine (0.20 mL, 1.86 mmol), andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (108 mg, 0.93 mmol). Afterstirring for 30 minutes, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (166 mg, 0.87 mmol) was added and the solution was stirredfor 72 hours. The solution was partitioned between ethyl acetate and H₂Oand the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with H₂O and saturated NaCl and dried overNa₂SO₄. Chromatography (on silica, ethyl acetate/hexane) provided theprotected hydroxamate as a white solid (150 mg, 43%). MS (CI) MH⁺calculated for C₂₈H₃₅N₃O₇S: 558, found 558.

Part F: To a solution of protected hydroxamate of part E (133 mg, 0.24mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (10 mL) andthe solution was stirred for 1.5 hours. The solution was diluted withethyl ether and the resulting precipitate was collected by vacuumfiltration to provide the title hydroxamate as a white solid (80 mg,66%). MS (CI) MH⁺ calculated for C₂₃H₂₇N₃O₆S: 474, found 474. HRMScalculated for C₂₃H₂₇N₃O₆S: 474.1699, found 474.1715. Analyticalcalculation for C₂₃H₂N₃O₆S.1.5HCl.1.5H₂O: C, 49.75; H, 5.72; N, 7.57; S,5.77; Cl, 9.58. Found: C, 49.78; H, 5.52; N, 8.05; S, 9.16; Cl, 5.76.

EXAMPLE 412 Preparation of1-cyclopropyl-4-[[4-[4-[[4-(2,3-dimethylphenyl)-1-piperazinyl]-carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidine-carboxamide,trihydrochloride

Part A: To a solution of the isonipecotic acid (10.5 g, 81.3 mmol) inH₂O (325 mL) was added sodium carbonate (8.37 g, 81.3 mmol) and thesolution was stirred until homogeneous. To this solution was addeddi-tert-butyl dicarbonate (18.22 g, 83.5 mmol) in 1,4-dioxane (77 mL)dropwise, and the resulting solution was stirred for 72 hours at ambienttemperature. The solution was concentrated in vacuo and the resultingaqueous solution was washed with ethyl ether. The aqueous solution wasacidified to pH=2 with concentrated HCl. The solution was extracted withethyl ether and concentrated in vacuo provided a white solid.Recrystallization (ethyl acetate) provided N-Boc-isonipecotic acid as awhite solid (10 g, 54%)

Part B: To a solution of the N-Boc-isonipecotic acid of part A (2.14 g,9.33 mmol) in dichloromethane (19 mL) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.82 g,9.49 mmol), N-hydroxybenzotriazole (1.32 g, 9.77 mmol) and1-(2,3-xylyl)piperazine monohydrochloride (2.47 g, 10.89 mmol). After 30minutes diisopropylethylamine (0.74 mL, 20.7 mmol) was added, and thesolution was stirred for 18 hours. The solution was concentrated invacuo and the residue was dissolved into ethyl acetate and washed with1M HCl, saturated NaHCO₃ and saturated NaCl. The solution was dried overMgSO₄. Recrystallization (ethyl acetate/hexane) provided the amide as anoff-white solid (2.65 g, 71%).

Part C: To a solution of the amide of part B (1.0 g, 3.75 mmol) indichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and thesolution was stirred for 15 minutes. The solution was concentrated invacuo and the resulting oil was dissolved into N,N-dimethylacetamide (10mL). To this solution was added the product of Example 398, Part A (979mg, 2.50 mmol) and cesium carbonate (3.67 g, 11.25 mmol) and thesolution was heated at one hundred and ten degrees Celsius for 17 hours.The solution was partitioned between ethyl acetate and H₂O. The organiclayer was washed with H₂O and saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provided the piperidine compound as a white solid(1.89 g, quantitative yield). MS (CI) MH⁺ calculated for C₃₅H₄₈N₄O₅S:637, found 637.

Part D: To a solution of the piperidine compound of part C (1.89 g) inethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide(1.0 g, 25 mmol) in H₂O (5 mL). The solution was heated to fifty degreesCelsius for 8 hours and at sixty-two degrees Celsius for 8 hours. Thesolution was concentrated in vacuo and the residue was diluted with H₂Oand acidified to pH=3 with 3M HCl. The resulting precipitate wascollected by vacuum filtration to provide the acid as a white solid(1.16 g, 65%). MS (CI) MH⁺ calculated for C₃₃H₄₄N₄O₅S: 609, found 609.

Part E: To a solution of the acid of part D (1.16 g, 1.62 mmol) inN,N-dimethylformamide (10 mL) were added N-hydroxybenzotriazole (262 mg,1.94 mmol), 4-methylmorpholine (0.90 mL, 8.2 mmol) andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (284 mg, 2.4 mmol). Afterstirring for 45 minutes, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (334 mg, 2.2 mmol) was added and the solution was stirredfor 18 hours at ambient temperature. The solution was partitionedbetween ethyl acetate and H₂O and the organic layer was washed with H₂Oand saturated NaCl and dried over Na₂SO₄. Trituration (dichloromethane)provided the protected hydroxamate as a white solid (850 mg, 75%). MS(CI) MH⁺ calculated for C₃₈H₅₃N₅O₆S: 708, found 708. Analyticalcalculation for C₃₈H₅₃N₅O₆S.0.5H₂O: C, 63.66; H, 7.59; N, 9.77; S, 4.47.Found: C, 63.68; H, 7.54; N, 9.66; S, 4.67.

Part F: To a solution of the protected hydroxamate of part E (746 mg,1.07 mmol) in methanol (10 mL) was added 4M HCl in 1,4-dioxane (10 mL)and the solution was stirred for one hour. The resulting solid wascollected by vacuum filtration and washed with ethyl ether to providethe title compound as a white solid (650 mg, 83%). MS (CI) MH⁺calculated for C₃₃H₄₉N₅O₅S: 624, found 624. HMS calculated forC₃₃H₄₉N₅O₅S: 624.3220, found 624.3253. Analytical calculation forC₃₃H₄₅N₅O₅S.3.5HCl.H₂O: C, 51.82; H, 6.59; N, 9.16. Found: C, 52.04; H,6.30; N, 8.96.

EXAMPLE 413 Preparation of4-[[4-[4-[[4-(2,3-dimethylphenyl)-1-piperazinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidine-carboxamide,trihydrochloride

Part A: To a solution of the isonipecotic acid (10.5 g, 81.3 mmol) inH₂O (325 mL) was added sodium carbonate (8.37 g, 81.3 mmol) and thesolution was stirred until homogeneous. To this solution was addeddi-tert-butyl dicarbonate (18.22 g, 83.5 mmol) in 1,4-dioxane (77 mL)dropwise and the resulting solution was stirred for 72 hours at ambienttemperature. The solution was concentrated in vacuo and the resultingaqueous solution was washed with ethyl ether. The aqueous solution wasacidified to pH=2 with concentrated HCl. The solution was extracted withethyl ether and concentration in vacuo provided a white solid.Recrystallization (ethyl acetate) provided N-Boc-isonipecotic acid as awhite solid (10 g, 54%).

Part B: To a solution of the N-Boc-isonipecotic acid of part A (2.14 g,9.33 mmol) in dichloromethane (19 mL) were added1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (1.82 g,9.49 mmol), N-hydroxybenzotriazole (1.32 g, 9.77 mmol) and1-(2,3-xylyl)piperazine monohydrochloride (2.47 g, 10.89 mmol). After 30minutes, diisopropylethylamine (0.74 mL, 20.7 mmol) was added and thesolution was stirred for 18 hours. The solution was concentrated invacuo and the residue was dissolved into ethyl acetate and washed with1M HCl, saturated NaHCO₃ and saturated NaCl. The solution was dried overMgSO₄. Recrystallization (ethyl acetate/hexane) provided the amide as anoff-white solid (2.65 g, 71%).

Part C: To a solution of the amide of part B (965 mg, 2.41 mmol) indichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and thesolution was stirred for 15 minutes. The solution was concentrated invacuo and the resulting oil was dissolved into N,N-dimethylacetamide (10mL). To this solution were addedethyl-4-[[4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(600 mg, 1.61 mmol) and cesium carbonate (2.75 g, 8.43 mmol), and thesolution was heated at one hundred and ten degrees Celsius for 20 hours.The solution was partitioned between ethyl acetate and H₂O. The organiclayer was washed with H₂O and saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provided the piperidine compound as a white solid(1.26 g, quantitative yield). MS (CI) MH⁺ calculated for C₃₅H₅₀N₄O₆S:655, found 655.

Part D: To a solution of the piperidine compound of part C (1.26 g) inethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide(644 mg, 16 mmol) in H₂O (5 mL). The solution was heated to sixtydegrees Celsius for 8 hours and at sixty-two degrees Celsius for 8hours. The solution was concentrated in vacuo and the residue wasdiluted with H₂O and acidified to pH=3 with 3M HCl. The resultingprecipitate was collected by vacuum filtration to provide the acid as awhite solid (650 mg, 65%). MS (CI) MH⁺ calculated for C₃₃H₄₆N₄O₆S: 627,found 627.

Part E: To a solution of the acid of part D (620 g, 0.94 mmol) inN,N-dimethylformamide (10 mL) were added N-hydroxybenzotriazole (152 mg,1.13 mmol), 4-methylmorpholine (0.52 mL, 4.7 mmol) andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (165 mg, 1.4 mmol). Afterstirring for 45 minutes, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (252 mg, 1.32 mmol) was added and the solution was stirredfor 18 hours at ambient temperature. The solution was partitionedbetween ethyl acetate and H₂O, and the organic layer was washed with H₂Oand saturated NaCl, and dried over Na₂SO₄. Concentration in vacuoprovided the protected hydroxamate as a white solid (641 mg, 94%). MS(CI) MH⁺ calculated for C₃₈H₅₅N₅O₇S: 726, found 726.

Part F: To a solution of the protected hydroxamate of part E (630 mg,0.87 mmol) in methanol (8 mL) was added 4M HCl in 1,4-dioxane (10 mL)and the solution was stirred for one hour. The resulting solid wascollected by vacuum filtration and washed with ethyl ether to providethe title compound as a white solid (624 mg, 83%). MS (CI) MH⁺calculated for C₃₃H₄₇N₅O₆S: 642, found 642.

EXAMPLE 414 Preparation ofN-hydroxy-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part E (6.0 g, 15.4mmol) and powdered K₂CO₃ (8.0 g, 38.5 mmol) in N,N-dimethylformamide (70mL) was added 4-isopropyl phenol (5.24 g, 38.5 mmol) at ambienttemperature, and the solution was heated to ninety degrees Celsius for32 hours. The solution was concentrated under high vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith 1N NaOH, H₂O and dried over MgSO₄. Chromatography on silica elutingwith ethyl acetate/hexane provided the diaryl ether as light yellow gel(6.89 g, 87%).

Part B: To a solution of diaryl ether of part A (6.89 g, 14.7 mmol) inethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147mmol) in H₂O (28 mL) from an addition funnel at ambient temperature. Thesolution was then heated to sixty degrees Celsius for 17 hours andambient temperature for 24 hours. The solution was concentrated in vacuoand diluted with water. The aqueous layer was extracted with ether andacidified to pH=2. Vacuum filtration of white precipitation provided theacid as a white solid (6.56 g, quantitative yield).

Part C: To the solution of acid of part B (6.56 g, 14.86 mmol), N-methylmorpholine (6.5 mL, 59.4 mmol), 1-hydroxybenzotriazole (6.0 g, 44.6mmol) and O-tetrahydropyranyl hydroxyl amine (3.5 g, 29.7 mmol) inN,N-dimethylformamide (50 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.5 g,44.6 mmol), and the solution was stirred at ambient temperature for 20hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated aqueous NaHCO₃, H₂O and dried over MgSO₄. Concentration invacuo and chromatography on silica eluting with ethyl acetate/hexaneprovided the tetrahydropyranyl-protected hydroxamate as a white foam(8.03 g, quantitative yield).

Part D: To a solution of 4N HCl in dioxane (37 mL, 149 mmol) was added asolution of the tetrahydropyranyl-protected hydroxamate of part C (8.03g, 14.9 mmol) in methanol (5 mL) and dioxane (15 mL) and the solutionwas stirred at ambient temperature for 3 hours. Concentration in vacuoand trituration with diethyl ether provided the title compound as awhite solid (5.0 g, 71.1%). Analytical calculation forC₂₄H₂₈N₂O₅S.HCl.0.9H₂O: C, 56.61; H, 6.10; N, 5.50; S, 6.30. Found: C,56.97; H, 6.05; N, 5.41; S, 5.98. HRMS MH⁺ calculated for C₂₄H₂₈N₂O₅S:457.1797, found 457.1816.

EXAMPLE 415 Preparation of4-[[4-(1,3-benzodioxol-5-yloxy)phenyl)sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (25 g, 67.3mmol) and powdered K₂CO₃ (23.3 g, 169 mmol) in N,N-dimethylformamide(150 mL) was added sesamol (23.2 g, 168 mmol) at ambient temperature andsolution was heated to ninety degrees Celsius for 25 hours. The solutionwas concentrated under high vacuum and the residue was dissolved inethyl acetate. The organic layer was washed with 1N NaOH, H₂O and driedover MgSO₄. Chromatography on silica eluting with ethyl acetate/hexaneprovided the desired diaryl ether as light yellow gel (33.6 g, 93.6%).

Part B: To a solution of diaryl ether of part A (4.0 g, 7.4 mmol) indichloromethane (7 mmol) cooled to zero degrees Celsius was addedtrifluroacetic acid (7 mL) and the solution was stirred at ambienttemperature for 2 hours. Concentration in vacuo provided the aminetrifluoroacetate salt as a light yellow gel. To the solution of thetrifluoroacetate salt and K₂CO₃ (3.6 g, 26 mmol) inN,N-dimethylformamide (50 mL) was added 2-bromoethyl methyl ether (1.8mL, 18.7 mmol) and the solution was stirred at ambient temperature for36 hours. The N,N-dimethylformamide was evaporated under high vacuum andresidue was diluted with ethyl acetate. The organic layer was washedwith water and dried over Mg₂SO₄. Concentration in vacuo provided themethoxyethyl amine as a light yellow gel (3.7 g, quantitative yield).

Part C: To a solution of methoxyethyl amine of part B (3.7 g, 7.5 mmol)in ethanol (7 mL) and tetrahydrofuran (7 mL) was added NaOH (3.0 g, 75mmol) in H₂O (15 mL) from an addition funnel at ambient temperature. Thesolution was then heated to sixty degrees Celsius for 19 hours andambient temperature for 12 hours. The solution was concentrated in vacuoand diluted with water. The aqueous layer was extracted with ether andacidified to pH=2. Vacuum filtration of the white precipitate providedthe acid as a white solid (4.0 g, quantitative yield).

Part D: To a solution of the acid of part C (4.0 g, 7.5 mmol), N-methylmorpholine (3.3 mL, 30 mmol), 1-hydroxybenzotriazole (3.0 g, 22.5 mmol)and O-tetrahydropyranyl hydroxyl amine (1.8 g, 15 mmol) inN,N-dimethylformamide (100 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.3 g,22.5 mmol), and the solution was stirred at ambient temperature for 4days. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated aqueous NaHCO₃, H₂O and dried over Mg₂SO₄. Concentration invacuo and chromatography on silica eluting with ethyl acetate/hexaneprovided the tetrahydropyranyl-protected hydroxamate as a white foam(2.40 g, 57.1%).

Part E: To a solution of 4N HCl in dioxane (11 mL, 43 mmol) was added asolution of the tetrahydropyranyl-protected hydroxamate of part D (2.4g, 4.3 mmol) in methanol (2 mL) and dioxane (6 mL) and the solution wasstirred at ambient temperature for 3 hours. Concentration in vacuo andtrituration with ether provided hydroxamate hydrochloride salt as awhite solid (1.88 g, 85.8%). Analytical calculation forC₂₂H₂₆N₂O₈S.HCl.H₂O: C, 49.58; H, 5.48; N, 5.26; S, 6.02. Found: C,49.59; H, 5.53; N, 5.06; S, 5.71. HRMS MH⁺ calculated for C₂₂H₂₆N₂O₈S:479.1488, found 479.1497.

EXAMPLE 416 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl}-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (30 g, 161mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius wasadded trifluroacetic acid (25 mL) and the solution was stirred atambient temperature for 1 hour. Concentration in vacuo provided theamine trifluoroacetate salt as a light yellow gel. To the solution ofthe trifluoroacetate salt and K₂CO₃ (3.6 g, 26 mmol) inN,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred atambient temperature for 36 hours. Then, N,N-dimethylformamide wasevaporated under high vacuum and the residue was diluted with ethylacetate. The organic layer was washed with water and dried over MgSO₄.Concentration in vacuo provided the methoxyethyl amine as a light yellowgel (26.03 g, 86.8%).

Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of part Aand powdered K₂CO₃ (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL)was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambienttemperature and the solution was heated to ninety degrees Celsius for 25hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed with 1NNaOH, H₂O and dried over MgSO₄. Chromatography on silica eluting withethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone asa light yellow gel (7.81 g, 91.5%).

Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of partB (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) wasadded NaOH (5.88 g, 147 mmol) in H₂O (28 mL) from an addition funnel atambient temperature. The solution was then heated to sixty degreesCelsius for 18 hours. The solution was concentrated in vacuo and dilutedwith water. The aqueous layer was extracted with ether and acidified topH=2. Vacuum filtration of white precipitation provided the acid as awhite solid (5.64 g, 73.3%).

Part D: To a solution of the acid of part C (5.64 g, 10.8 mmol),N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g,32.4 mmol) and O-tetrahydropyranyl hydroxyl amine (2.5 g, 21.6 mmol) inN,N-dimethylformamide (50 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g,32.4 mmol), and the solution was stirred at ambient temperature for 24hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated aqueous NaHCO₃, H₂O and dried over MgSO₄. Concentration invacuo and chromatography on silica eluting with ethyl acetate/hexaneprovided the tetrahydropyranyl-protected hydroxamate as a white foam(6.65 g, quantitative yield).

Part E: To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added asolution of the tetrahydropyranyl-protected hydroxamate of part D (6.65g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred atambient temperature for 3 hours. Concentration in vacuo and triturationwith diethyl ether provided the title compound as a white solid (4.79 g,78.2%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.HCl.0.5H₂O: C, 46.85;H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.

EXAMPLE 417 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride

Part A: To a solution ofethyl-4-[(4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(1.47 g, 3.9 mmol) and powdered K₂CO₃ (1.6 g, 11.7 mmol) inN,N-dimethylformamide (15 mL) was added 4-isopropylphenol (1.07 g, 7.8mmol) at ambient temperature and the solution was heated to ninetydegrees Celsius for 24 hours. The solution was concentrated under highvacuum and the residue was dissolved in ethyl acetate. The organic layerwas washed with 1N NaOH, H₂O and dried over MgSO₄. Chromatography onsilica eluting with ethyl acetate/hexane provided the diaryl ether as alight yellow gel (1.77 g, 92.2%).

Part B: To a solution of diaryl ether of part A (1.77 g, 3.6 mmol) inethanol (3.5 mL) and tetrahydrofuran (3.5 mL) was added NaOH (1.46 g, 36mmol) in H₂O (7 mL) at ambient temperature. The solution was then heatedto sixty degrees Celsius for 18 hours. The solution was concentrated invacuo and diluted with water. The aqueous layer was extracted withdiethyl ether and acidified to pH=2. Vacuum filtration of the whiteprecipitate provided the acid as a white solid (1.39 g, 83.7%).

Part C: To the solution of the acid of part B (1.39 g, 3.0 mmol),N-methyl morpholine (1 mL, 9 mmol), 1-hydroxybenzotriazole (1.22 g, 9mmol) and O-tetrahydropyranyl hydroxyl amine (0.72 g, 6.0 mmol) inN,N-dimethylformamide (90 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.72 g,9.0 mmol), and solution was stirred at ambient temperature for 48 hours.The solution was concentrated under high vacuum and the residue wasdissolved in ethyl acetate. The organic layer was washed with saturatedaqueous NaHCO₃, H₂O and dried over MgSO₄. Concentration in vacuo andchromatography on silica eluting with ethyl acetate/hexane provided thetetrahydropyranyl-protected hydroxamate as a white foam (1.65 g, 98.2%).

Part D: To a solution of 4N HCl in dioxane (7.35 mL, 29.4 mmol) wasadded a solution of the tetrahydropyranyl-protected hydroxamate of partC (1.65 g, 2.94 mmol) in methanol (1 mL) and dioxane (3 mL), and thesolution was stirred at ambient temperature for 3 hours. Concentrationin vacuo and trituration with diethyl ether provided the title compoundas a white solid (1.2 g, 79.5%). Analytical calculation forC₂₄H₃₂N₂O₆S.HCl.0.5H₂O: C, 55.22; H, 6.56; N, 5.37; S, 6.14. Found: C,55.21; H, 6.41; N, 5.32; S, 6.18.

EXAMPLE 418 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethyl)-phenoxy]phenyl]sulfonyl}-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution ofethyl-4-[(4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(6 g, 16.0 mmol) and powdered K₂CO₃ (4.44 g, 32 mmol) inN,N-dimethylformamide (50 mL) was added 4-trifluoromethylphenol (5.72 g,32 mmol) at ambient temperature, and the solution was heated to ninetydegrees Celsius for 48 hours. The solution was concentrated under highvacuum and the residue was dissolved in ethyl acetate. The organic layerwas washed with 1N NaOH, H₂O and dried over MgSO₄. Chromatography onsilica eluting with ethyl acetate/hexane provided the desired diarylether as a light yellow gel (2.66 g, 32.1%).

Part B: To a solution of the diaryl ether of part A (1.5 g, 2.9 mmol) inethanol (3 mL) and tetrahydrofuran (3 mL) was added NaOH (1.22 g, 29mmol) in H₂O (6 mL) at ambient temperature. The solution was then heatedto sixty degrees Celsius for 18 hours. The solution was concentrated invacuo and diluted with water. The aqueous layer was extracted withdiethyl ether and acidified to pH=2. Vacuum filtration of the whiteprecipitate provided the desired acid as a white solid (1.0 g, 70.9%).

Part C: To the solution of the acid of part B (1.0 g, 2.05 mmol),N-methyl morpholine (0.68 mL, 6.1 mmol), 1-hydroxybenzotriazole (0.84 g,6.15 mmol) and O-tetrahydropyranyl hydroxyl amine (0.5 g, 4.1 mmol) inN,N-dimethylformamide (20 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.18 g, 6mmol), and solution was stirred at ambient temperature for 24 hours. Thesolution was concentrated under high vacuum and the residue wasdissolved in ethyl acetate. The organic layer was washed with saturatedNaHCO₃, H₂O and dried over MgSO₄. Concentration in vacuo andchromatography on silica eluting with ethyl acetate/hexane provided thetetrahydropyranyl-protected hydroxamate as a white foam (1.16 g, 96.7%).

Part D: To a solution of 4N HCl in dioxane (5 mL, 20 mmol)) was added asolution of the tetrahydropyranyl-protected hydroxamate of part C (1.16g, 2 mmol) in methanol (1 mL) and dioxane (3 mL) and was stirred atambient temperature for 3 hours. Concentration in vacuo and triturationwith diethyl ether provided the title compound as a white solid (0.79 g,74.5%). Analytical calculation for C₂₂H₂₅N₂O₆SF₃.HCl: C, 49.03; H, 4.86;N, 5.20; S, 5.95. Found: C, 48.85; H, 4.60; N, 5.22; S, 6.13.

EXAMPLE 419 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution ofethyl-4-[(4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(5 g, 13.4 mmol) and powdered K₂CO₃ (3.7 g, 27 mmol) inN,N-dimethylformamide (20 mL) was added 4-(trifluoromethylthio)phenol(3.9 g, 20 mmol) at ambient temperature, and solution was heated toninety degrees Celsius for 24 hours. The solution was concentrated underhigh vacuum, and the residue was dissolved in ethyl acetate. The organiclayer was washed with 1N NaOH, H₂O and dried over MgSO₄. Chromatographyon silica eluting with ethyl acetate/hexane provided the desired diarylether as a light yellow gel (5.94 g, 81.04%).

Part B: To a solution of the diaryl ether of part A (5.94 g, 210 mmol)in ethanol (10 mL) and tetrahydrofuran (10 mL) was added NaOH (4.34 g,108 mmol) in H₂O (20 mL) dropwise at ambient temperature. The solutionwas then heated to sixty degrees Celsius for 24 hours and ambienttemperature for anther 24 hours. The solution was concentrated in vacuoand diluted with water. The aqueous layer was extracted with diethylether and acidified to pH=2. Vacuum filtration of the white precipitateprovided the acid as a white solid (5.5 g, quantitative yield).

Part C: To the solution of the acid of part B (5.5 g, 10.8 mmol),N-methyl morpholine (3.6 mL, 32.4 mmol), 1-hydroxybenzotriazole (4.4 g,32.4 mmol) and O-tetrahydropyranyl hydroxyl amine (2.6 g, 21.8 mmol) inN,N-dimethylformamide (200 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g,32.4 mmol), and the solution was stirred at ambient temperature for 24hours. The solution was concentrated under high vacuum and the residuewas dissolved in ethyl acetate. The organic layer was washed withsaturated aqueous NaHCO₃, H₂O and dried over MgSO₄. Concentration invacuo and chromatography on silica eluting with ethyl acetate/hexaneprovided the tetrahydropyranyl-protected hydroxamate as a white foam(4.66 g, 69.8%).

Part D: To a solution of 4N HCl in dioxane (20 mL, 79 mmol)) was added asolution of the tetrahydropyranyl-protected hydroxamate of part C (4.65g, 7.9 mmol) in methanol (2.5 mL) and dioxane (8 mL) and was stirred atambient temperature for 3 hours. Concentration in vacuo and triturationwith diethyl ether provided the title compound as a white solid (3.95 g,92.1%). Analytical calculation for C₂₂H₂₅N₂O₆S₂F₃.HCl: C, 46.27; H,4.59; N, 4.91; S, 11.23. Found: C, 46.02; H, 4.68; N, 4.57; S, 11.11.

EXAMPLE 420 Preparation ofN-hydroxy-1-(1-methylethyl)-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (30 g, 161mmol) in dichloromethane (40 mL) cooled to zero degrees Celsius wasadded trifluroacetic acid (30 mL), and the solution was stirred atambient temperature for 1 hour. Concentration in vacuo provided thetrifluoroacetate salt as a light yellow gel. To the solution of thetrifluoroacetate salt and triethylamine (28 mL, 201 mmol) indichloromethane (250 mL) cooled to zero degrees Celsius, were addedacetone (24 mL, 320 mmol) and sodium triacetoxyborohydride (68 g, 201mmol) in small portions followed by addition of acetic acid (18.5 mL,320 mmol), and solution was stirred at ambient temperature for 48 hours.Then, the dichloromethane was evaporated under high vacuum and theresidue was diluted with diethyl ether. The organic layer was washedwith 1N NaOH, water and dried over MgSO₄. Concentration in vacuoprovided the isopropyl amine as a light yellow gel (21.03 g, 72.8%).

Part B: To a solution of isopropyl amine (4 g, 11.2 mmol) of part A andpowdered K₂CO₃ (3.09 g, 22.4 mmol) in N,N-dimethylformamide (30 mL) wasadded 4-isopropylphenol (3.05 g, 22 mmol) at ambient temperature and thesolution was heated to ninety degrees Celsius for 25 hours. The solutionwas concentrated under high vacuum and the residue was dissolved inethyl acetate. The organic layer was washed with 1N NaOH, H₂O and driedover MgSO₄. Chromatography on silica eluting with ethyl acetate/hexaneprovided the desired diaryl ether as a light yellow gel (5.10 g, 96.2%).

Part C: To a solution of the diaryl ether of part B (5.10 g. 10.77 mmol)in ethanol (10 mL) and tetrahydrofuran (10 mL) was added NaOH (4.3 g,108 mmol) in H₂O (20 mL) from an addition funnel at ambient temperature.The solution was then heated to sixty degrees Celsius for 24 hours andat ambient temperature for anther 24 hours. The solution wasconcentrated in vacuo and diluted with water. The aqueous layer wasextracted with diethyl ether and acidified to pH=2. Vacuum filtration ofthe white precipitate provided the desired acid as a white solid (4.80g, quantitative yield).

Part D: To the solution of the acid of part C (4.80 g, 10.8 mmol),N-methyl morpholine (3.6 mL, 32.4 mmol), 1-hydroxybenzotriazole (4.4 g,32.4 mmol) and O-tetrahydropyranyl hydroxyl amine (2.6 g, 21.6 mmol) inN,N-dimethylformamide (100 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.17 g,32.4 mmol), and the solution was stirred at ambient temperature for 7days. The solution was filtered to eliminate the unreacted startingmaterial and the filtrate was concentrated under high vacuum. Theresidue was dissolved in ethyl acetate and the organic layer was washedwith saturated aqueous NaHCO₃, H₂O and dried over MgSO₄. Concentrationin vacuo and chromatography on silica eluting with ethyl acetate/hexaneprovided the tetrahydropyranyl-protected hydroxamate as a white foam(2.45 g, 41.7%).

Part E: To a solution of 4N HCl in dioxane (11.2 mL, 45 mmol) was addeda solution of the tetrahydropyranyl-protected hydroxamate of part D(2.45 g, 11.03 mmol) in methanol (4 mL) and dioxane (8 mL) and wasstirred at ambient temperature for 3 hours. Concentration in vacuo andtituration with diethyl ether provided the title compound as a whitesolid (2.01 g, 89.7%). Analytical calculation forC₂₄H₃₂N₂O₅S.HCl.0.5H₂O: C, 56.96; H, 6.77; N, 5.54; S, 6.34. Found: C,56.58; H, 6.71; N, 5.44; S, 6.25.

EXAMPLE 421 Preparation of4-[[4-(1,3-benzodioxol-5-yloxy)phenyl]sulfonyl]-1-cyclopropyl-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (9.0 g, 22.0mmol) in DMF (30 mL) was added K₂CO₃ (4.55 g, 33 mmol), and sesamol(4.55 g, 33 mmol). The solution was stirred at ninety degrees Celsiusfor 24 hours. The solution was diluted with H₂O (400 mL) and extractedwith ethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel eluting with 10% ethyl acetate/hexane provided the desiredester as an oil (9.3 g, 79%). HRMS MH⁺ calculated for C₂₆H₃₁NSO₉:534.1798, found 534.1796.

Part B: To a solution of the ester of part A (9.3 g, 17 mmol) in ethylacetate (100 mL) cooled to zero degrees C. was bubbled gaseous HCl for10 minutes. The reaction was stirred at this temperature for 0.5 hours.The solution was concentrated in vacuo to give the hydrochloride salt(7.34 g, 92%). MS MH⁺ calculated for C₂₁H₂₃NSO₇: 434.1273, found434.1285.

Part C: To a solution of the hydrochloride salt of part B (7.34 g, 15.6mmol) in methanol (60 mL) was added acetic acid (8.94 mL, 156 mmol), aportion (about 2 g) of 4-Å molecular sieves,(1-ethoxycyclopropyl)-oxytrimethyl silane (18.82 mL, 93.6 mmol) andsodium cyanoborohydride (4.41 g, 70.2 mmol). The solution was refluxedfor B hours. The precipitate was removed by filtration and the filtrateconcentrated in vacuo. The residue was diluted with H₂O (400 mL) andextracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo.Chromatography on silica gel eluting with 100% ethyl acetate) providedthe desired cyclopropyl amine as a solid (7.9 gm, 100%). MS MH⁺calculated for C₂₄H₂₇NSO₇: 474.1586, found 474.1599.

Part D: To a solution of cyclopropyl amine from part C (7.9 g, 16.7mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added asolution of NaOH (6.68 g, 166.8 mmol) in water (30 mL) and the solutionwas heated at sixty degrees Celsius for 18 hours. The solution wasconcentrated in vacuo and the aqueous residue was acidified to pH=3. Theresulting precipitate was filtered to give desired carboxylic acid (6.14g, 76%). MS MH⁺ calculated for C₂₂H₂₅NSO₇: 446.1273. Found 446.1331.

Part E: To a solution of the carboxylic acid of part D (6.14 g, 12.7mmol) in DMF (60 mL) was added 1-hydroxybenzotriazole (2.06 g, 15.2mmol), N-methyl morpholine (4.2 mL, 38.0 mmol) and O-tetrahydropyranylhydroxyl amine (2.23 g, 19.0 mmol) followed by1,3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.41 g,17.8 mmol). The solution was stirred at ambient temperature for 18hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel eluting with 40% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a solid (6.67 q, 96%).

Part F: To a solution of tetrahydropyranyl-protected hydroxamate of partE (6.67 g, 12.0 mmol) in dioxane (70 mL) was added 4 N HCl/dioxane (6.6mL). After stirring at ambient temperature for 3 hours, the solution wasconcentrated in vacuo. Chromatography on a C18 reverse phase column,eluting with acetonitrile/(HCl)water, provided a white solid 10 (4.21gm, 69%). MS MH⁺ calculated for C₂₂H₂₄N₂SO₇: 461.1382. Found 461.1386.

EXAMPLE 422 Preparation of1-cyclopropyl-4-[[4-(4-ethoxyphenoxy)phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (8.0 g, 19.2mmol) in DMF (30 mL) was added K₂CO₃ (4.00 g, 28.8 mmol) and4-ethoxyphenol (3.99 g, 28.8 mmol). The solution was stirred at ninetydegrees Celsius for 24 hours. The solution was diluted with H₂O (400 mL)and extracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo.Chromatography on silica gel eluting with 10% ethyl acetate/hexaneprovided the desired ester as an oil (9.62 g, 94%). MS MH⁺ calculatedfor C₂₇H₃₅NSO₈: 534.2162. Found 534.2175.

Part B: To a solution of ester of part A (9.62 g, 18 mmol) in ethylacetate (100 mL) cooled to zero degrees Celsius was bubbled gaseous HClfor 5 minutes. The reaction was stirred at this temperature for 0.5hours. The solution was then concentrated in vacuo to give a thehydrochloride salt (8.1 g, 96%). MS MH⁺ calculated for C₂₂H₂₇NSO₆:434.1637. Found 434.1637.

Part C: To a solution of the hydrochloride salt of part B (8.1 g, 17.2mmol) in methanol (70 mL) was added acetic acid (9.86 mL, 172 mmol), aportion of 4-Å molecular sieves (ca. 2 g),(1-ethoxycyclopropyl)-oxytrimethyl silane (20.7 mL, 103 mmol) and sodiumcyanoborohydride (4.86 g, 77.4 mmol). The solution was refluxed for 8hours. The precipitate was removed by filtration and the filtrate wasconcentrated in vacuo. The residue was diluted with H₂O (400 mL) andextracted with ethyl acetate. The organic layer was washed with 1 NNaOH, saturated NaCl and dried over MgSO₄, filtered and concentrated invacuo. Trituration with diethyl ether provided the desired cyclopropylamine as a white solid (6.84 g, 84%).

Part D: To a solution of cyclopropyl amine from part C (6.84 gm, 14.0mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added asolution of NaOH (5.60 g, 140 mmol) in water (30 mL) and the solutionwas heated at sixty degrees Celsius for 18 hours. The solution wasconcentrated in vacuo and the aqueous residue was acidified to pH=3.Filtration gave the desired acid (6.07 g, 88%). MS MH⁺ calculated forC₂₂H₂₇NSO₆: 446. Found 446.

Part E: To a solution of the acid of part D (6.07 g, 12.6 mmol) in DMF(60 mL) was added 1-hydroxybenzotriazole (2.04 g, 15.1 mmol), N-methylmorpholine (4.15 mL, 37.8 mmol) and O-tetrahydropyranyl hydroxyl amine(2.21 g, 18.9 mmol) followed by1,3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.38 g,17.6 mmol). The solution was stirred at ambient temperature for 18hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel eluting with 60% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white foam (6.29 g, 92%).MS MH⁺ calculated for C₂₈H₃₆N₂SO₇: 545.2321. Found 545.2316.

Part F: To a solution of the tetrahydropyranyl-protected hydroxamate ofpart E (2.84 g, 5.0 mmol) in dioxane (40 mL) was added 4 N HCl/dioxane(30 mL). After stirring at ambient temperature for 2.5 hours, thesolution was concentrated in vacuo. Trituration of the resulting solidwith diethyl ether and filtration gave the desired hydroxamate as awhite solid (2.33 g, 90%). MS M⁺ calculated for C₂₃H₂₈N₂SO₆: 460.1677.Found 460.1678.

EXAMPLE 423 Preparation of4-[[4-(cyclohexylthio)phenyl]sulfonyl]-N-hydroxy-1-(methylsulfonyl)-4-piperidinecarboxamide

Part A: To a solution of the product of Example 9, Part D (10.0 g, 24.0mmol) in DMF (20 mL) was added K₂CO₃ (4.99 g, 36.0 mmol), cyclohexylmercaptan (4.40 g, 36.0 mmol). The solution was stirred at ninetydegrees Celsius for 48 hrs. The solution was diluted with H₂O (400 mL)and extracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo.Trituration with ethanol provided the desired sulfide as a white solid(7.16 g, 58%).

Part B: To a solution of sulfide from part B (9.46 g, 18.5 mmol) inethanol (30 mL) and tetrahydrofuran (30 mL) was added a solution of NaOH(7.39 g, 185 mmol) in water (15 mL) and the solution was heated atsixty-five degrees Celsius for 18 hours. The solution was concentratedin vacuo and the aqueous residue was acidified to pH=3.5. The resultingwhite solid was collected by filtration washed with H₂O and ethyl etherto give desired carboxylic acid (8.57 g, 95%).

Part C: To a solution of carboxylic acid of part B (8.3 g, 17.0 mmol) inethyl acetate (200 mL) cooled to zero degrees Celsius was bubbledgaseous HCl for 15 min. The reaction was then stirred at thistemperature for 0.5 hour. The solution was concentrated in vacuo toafford a residue which was triturated with diethyl ether to afford thedesired hydrochloride salt as a white solid (7.03 g, 98%). MS MH+calculated for C₁₈H₂₅NS₂O₄: 384.1303. Found 384.1318.

Part D: To a solution of the hydrochloride salt of part C (1.0 g, 2.4mmol) was added N-methyl morpholine (654 mL, 5.9 mmol) followed by mesylchloride (280 mL, 3.6 mmol) in methylene chloride (20 mL). The solutionwas stirred at ambient temperature for 18 hours. The solution wasdiluted with H₂O (400 mL) and extracted with methylene chloride. Theorganic layer was washed with water, saturated NaCl and dried overMgSO₄, filtered and concentrated in vacuo to yield the desiredmethanesulfomanide as a foam (1.0 g, quantitative yield).

Part E: To a solution of the methanesulfonamide of part D (1.3 g, 2.9mmol) in DMF (30 mL) was added 1-hydroxybenzotriazole (474 mg, 3.5mmol), N-methyl morpholine (956 mL, 8.7 mmol), tetrahydropyranylhydroxyl amine (509 mg, 4.3 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (778 mg,4.06 mmol). The solution was stirred at ambient temperature for 18hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel eluting with 30% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white foam (1.05 g, 82%).

Part F: To a solution of the tetrahydropyranyl-protected hydroxamate ofpart E (1.05 g, 1.97 mmol) in dioxane (30 mL) was added 4 N HCl/dioxane(10 mL). After stirring at ambient temperature for 2.5 hours, thesolution was concentrated in vacuo. Chromatography on C18 reverse phasecolumn eluting with acetonitrile/(HCl) water provided a white solid (602mg, 64%). MS M⁺ for C₁₉H₂₈NS₃O₆: 477, found 477.

EXAMPLE 424 Preparation ofN-hydroxy-1-(methylsulfonyl)-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide

Part A: To a solution of the product of Example 9, Part D (40.0 g, 96.0mmol) in DMF (200 mL) was added K₂CO₃ (20 g, 144 mmol) and thiophenol(22.2 g, 144 mmol). The solution was stirred at ambient temperature for24 hrs. The solution was then diluted with H₂O (1 L) and extracted withethyl acetate. The organic layer was washed with water, saturated NaCland dried over MgSO₄, filtered and concentrated in vacuo. Chromatography(on silica, elueting with 15% ethyl acetate/hexane) provided the desiredsulfide as a white solid (44.4 g, 91%).

Part B: To a solution of sulfide of part A (31.2 g, 6.6 mmol) in ethylacetate (500 mL) cooled to zero degrees Celsius was bubbled gaseous HClfor 30 minutes. The reaction was stirred at this temperature for 1.5hours. The solution was concentrated in vacuo and resulting solid wastriturated with diethyl ether to provide the hydrochloride salt as awhite solid (26.95 g, 96%).

Part C: To a solution of the hydrochloride salt of part B (2.0 g, 4.7mmol), were added N-methyl morpholine (1.29 mL, 11.7 mmol), followed bymesyl chloride (550 mL, 7.05 mmol) in methylene chloride (35 mL). Thesolution was stirred at ambient temperature for 48 hours. The solutionwas diluted with H₂O (400 mL) and extracted with methylene chloride. Theorganic layer was washed with water, saturated NaCl and dried overMgSO₄, filtered and concentrated in vacuo to yield the desiredmethanesulfonamide as a white solid (2.17 gm, 96%).

Part D: To a solution of the methane sulfonamide from part C (2.1 g, 4.3mmol) in ethanol (25 mL) and tetrahydrofuran (25 mL) was added asolution of NaOH (1.72 g, 43 mmol) in water (10 mL) and the solution washeated at sixty degrees Celsius for 18 hours. The solution wasconcentrated in vacuo and the aqueous residue was acidified to pH=3.5.The resulting precipitate was filtered to give the desired carboxylicacid as a white solid (2.1 g, quantitative yield).

Part E: To a solution of the carboxylic acid of part D (1.98 g, 4.3mmol) in DMF (30 mL) were added 1-hydroxybenzotriazole (705 mg, 5.2mmol), N-methyl morpholine (1.54 mL, 12.9 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (755 mg, 6.5 mmol) followed by1-3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (1.17 g,6.1 mmol). The solution was stirred at ambient temperature for 5 days.The solution was diluted with H₂O (400 mL) and extracted with ethylacetate. The organic layer was washed with saturated NaCl and dried overMgSO₄, filtered and concentrated in vacuo. Chromatography on C18 reversephase column, eluting with acetonitrile/(HCl) water provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (1.86 g, 80%).HRMS MH⁺ calculated for C₂₄H₃₀N₂S₃O₇: 555.1293, found 555.1276.

Part F: To a solution of tetrahydropyranyl-protected hydroxamate of partE (1.86 g, 3.5 mmol) in dioxane (30 mL) and methanol (10 mL) was added 4N HCl/dioxane (20 mL). After stirring at ambient temperature for 2.5hours, the solution was concentrated in vacuo. Chromatography on a C18reverse phase column eluting with acetonitrile/(HCl) water provided thetitle compound as a white solid (1.48 gm, 91%). HRMS MH⁺ calculated forC₁₉H₂₂N₂S₃O₆: 471.0718 Found 471.0728.

EXAMPLE 425 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 398, Part A (6.97 g,19.6 mmol) in DMF (500 mL) was added K₂CO₃ (3.42 g, 18.0 mmol) and4-(triflouromethoxy)-phenol (3.7 g, 24.8 mmol). The solution was stirredat ninety degrees Celsius for 40 hours. The solution was diluted withH₂O (600 mL) and extracted with ethyl acetate. The organic layer waswashed with water, saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo to afford the desired diaryl ether as an oil (8.5g, quantitative). HRMS MH⁺ calculated for C₂₄H₂₆NSO₆F₃: 514.1511. Found514.1524.

Part B: To a solution of diaryl ether from part A (8.4 g, 16.4 mmol) inethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH(6.54 g, 164 mmol) in water (20 mL) and the solution was heated at sixtydegrees Celsius for 18 hours. The solution was concentrated in vacuo toremove most of organic solvents and the aqueous residue was acidified topH=4.0. The resulting precipitate was filtered to give the desiredfiltered to give the hydrochloride salt as a white solid (5.01 g, 63%).HRMS MH⁺ calculated for C₂₂H₂₂NSO₆F₃: 486.1198, found 486.1200.

Part C: To a solution of the hydrochloride salt of part B (5.0 g, 10.3mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (1.8 g, 15.4 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g,12.3 mmol). The solution was stirred at ambient temperature for 42hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel, eluting with 30% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (5.41 g, 89%).

Part D: To a solution of tetrahydropyranyl-protected hydroxamate of partC (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4N HCl/dioxane (50 mL). The reaction was stirred at ambient temperaturefor 2.5 hours, the solution was concentrated in vacuo. Trituration withdiethyl ether afforded the title compound as a white solid (4.02 g,81%). HRMS MH⁺ calculated for C₂₂H₂₃N₂SO₆F₃: 501.1307, found 501.1324.

EXAMPLE 426 Preparation of1-cyclopropyl-4-[(4-ethoxyphenyl)sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 398, Part A (5.87 g,16.5 mmol) in DMF (50 mL) was added K₂CO₃ (3.42 g, 24.7 mmol) andα,α,α-(trifluoromethyl)-p-cresol (4.01 g, 24.7 mmol). The solution wasstirred at ninety degrees Celsius for 48 hours. The solution was dilutedwith H₂O (400 mL) and extracted with ethyl acetate. The organic layerwas washed with water, saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo to give the crude product, containing a largepercentage of starting material (8.39 g). To this material (8.39 g) inethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH(6.75 g, 169 mmol) in water (20 mL) and the solution was heated at sixtydegrees Celsius for 18 hours. The solution was concentrated in vacuo andthe aqueous residue was acidified to pH=3.5. The resulting precipitatewas filtered to give the desired hydrochloride salt as a waxy solid(5.04 g, 64%).

Part B: To a solution of the hydrochloride salt of part A (5.0 g, 10.3mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.73 g, 12.8mmol), N-methyl morpholine (3.5 mL, 31.8 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (1.86 g, 15.9 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.84 g,14.8 mmol). The solution was stirred at ambient temperature for 18hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel eluting with 30% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (1.5 g, 32%).

Part C: To a solution of tetrahydropyranyl-protected hydroxamate of partD (1.5 g, 3.3 mmol) in dioxane (30 mL) and methanol (15 mL) was added 4N HCl/dioxane (50 mL). The reaction was stirred at ambient temperaturefor 2 hours, then the solution was concentrated in vacuo. Trituration ofthe residue with diethyl ether afforded the title compound as a whitesolid (1.09 g, 81%). MS MH⁺ for C₁₇H₂₄N₂SO₅: 369 found 369.

EXAMPLE 427 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 398, Part A (5.96 g,15.0 mmol) in DMF (100 mL) was added K₂CO₃ (12.34 g, 38.0 mmol) andα,α,α-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution wasstirred ninety degrees Celsius for 28 hours. The solution was dilutedwith H₂O (400 mL) and extracted with ethyl acetate. The organic layerwas washed with water, saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo to afford desired aryl ether as an oil (7.54 g,quantitative).

Part B: To a solution of aryl ether from part A (7.54 g, 15.0 mmol) inethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH(6.06 g, 151.0 mmol) in water (20 mL) and the solution was heated atsixty degrees Celsius for 18 hours. The solution was concentrated invacuo and the aqueous residue was acidified to pH=2.0. The resultingprecipitate was filtered to give the desired hydrochloride salt as awhite solid (7.98 g, quantitative). MS MH⁺ calculated for C₂₂H₂₂NSO₅F₃:470, found 470.

Part C: To a solution of the hydrochloride salt of part B (7.60 g, 15.0mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (2.63 g, 22.5 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g,21.0 mmol). The solution was stirred at ambient temperature for 96hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica eluting with 30% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (5.93 g, 69%).

Part D: To a solution of tetrahydropyranyl-protected hydroxamate of partC (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30mL). The reaction was stirred at ambient temperature for 2 hours, thenthe solution was concentrated in vacuo. Trituration with diethyl etherafforded the title compound as a white solid (3.33 g, 96%). MS MH⁺calculated for C₂₂H₂₃N₂SO₅F₃: 485, found 485.

EXAMPLE 428 Preparation ofN-hydroxy-1-(1-methylethyl)-4-[[4-[4-(trifluoromethyl)-phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (30.0 g, 80.8mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (30mL) in methylene chloride (40 mL). The solution was stirred at ambienttemperature for two hours. The solution was concentrated in vacuo. Tothe residue dissolved in methylene chloride (150 mL) at zero degreesCelsius were added triethylamine (28.0 mL, 277 mmol), acetone (24.0 mL,413 mmol), sodium cyanoborohydride (68 g, 323.1 mmol) and acetic acid(18.5 mL, 308 mmol). The reaction mixture was stirred at ambienttemperature for 18 hours. The solution was diluted with 1N NaOH andextracted with ethyl ether. The organic layer was washed with 1N NaOH,water, saturated NaCl and dried over MgSO₄, filtered and concentrated invacuo to provided the desired isopropylamine (21.03 g, 72%).

Part B: To a solution of the isopropylamine of part A (4.04 g, 11.0mmol) in DMF (50 mL) was added CsCO₃ (10.75 g, 33.3 mmol) andα,α,α-trifluoro-p-cresol (2.67 g, 16.5 mmol). The solution was stirredat ninety degrees Celsius for 40 hours. The solution was diluted withH₂O (400 mL) and extracted with ethyl acetate. The organic layer waswashed with water, saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo. Chromatography on silica gel, eluting with 30%ethyl acetate/hexane, provided the desired diaryl ether as an oil (5.35g, 97%). HRMS MH⁺ calculated for C₂₄H₂₈NSO₅F₃: 500.1640, found:500.1678.

Part C: To a solution of the diaryl ether from part B (5.3 g, 10.6 mmol)in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution ofNaOH (4.2 g, 106.0 mmol) in water (25 mL) and the solution was heated atsixty degrees Celsius for 18 hours. The solution was concentrated invacuo and the aqueous residue was acidified to pH=3.0. The resultingprecipitate was filtered to give the desired hydrochloride salt as awhite solid (5.38 g, quantitative). MS MH⁺ calculated for C₂₂H₂₄NSO₅F₃:472.1406, found 471.472.1407.

Part D: To a solution of the hydrochloride salt of part C (5.4 g, 10.6mmol) in DMF (90 mL) were added 1-hydroxybenzotriazole (1.72 g, 12.3mmol), N-methyl morpholine (3.5 mL, 32.0 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (1.87 g, 15.9 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.B g,15.0 mmol). The solution was stirred at ambient temperature for 144hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel, eluting with 2% methanol/ethyl acetate, provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (2.74 g, 45%).HRMS MH⁺ calculated for C₂₇H₃₃N₂SO₅F₃: 571.2090, found 571.2103.

Part E: To a solution of tetrahydropyranyl-protected hydroxamate of partD (2.7 g, 4.7 mmol) in dioxane (50 mL) was added 4 N HCl/dioxane (20mL). The reaction was stirred at ambient temperature for 2 hours.Filtration afforded the title compound as a white solid (2.08 g, 84%).MS MH⁺ calculated for C₂₂H₂₅N₂SO₅F₃: 487, found 487.

EXAMPLE 429 Preparation of1-ethyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (48 g, 115.0mmol) in ethyl acetate (750 mL) cooled to zero degrees Celsius wasbubbled gaseous HCl for 45 minutes, and stirred at that temperature for7 hours. The solution was concentrated in vacuo to afford a residue thatwas triturated with diethyl ether to afford the desired hydrochloridesalt as a white solid (32.76 g, 81%).

Part B: To a solution of hydrochloride salt of part A (15.8 g, 45.0mmol) in DMF (75 mL) was added K₂CO₃ (12.4 g, 90.0 mmol) and bromoethane(3.4 mL, 45.0 mmol). The solution was stirred at ambient temperature for18 hours. The solution was diluted with H₂O (200 mL) and extracted withethyl acetate. The organic layer was washed with water, saturated NaCland dried over MgSO₄, filtered and concentrated in vacuo to provide thedesired ethyl amine as an oil (15.4 g, quantitative).

Part C: To a solution of ethyl amine of part B (5.2 g, 15.0 mmol) in DMF(50 mL) was added CsCO₃ (12.21 g, 37.5 mmol) andα,α,α-trifluoro-p-cresol (3.65 g, 23.0 mmol). The solution was stirredninety degrees Celsius for 25 hours. The solution was diluted with H₂O(400 mL) and extracted with ethyl acetate. The organic layer was washedwith water, saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo. Chromatography on silica gel, eluting with 20%ethyl acetate/hexane, provided the desired diaryl ether as an oil (7.3g, quantitative yield).

Part D: To a solution of diaryl ether from part C (7.3 g, 15.0 mmol) inethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH(6.0 g, 150 mmol) in water (30 mL), and the solution was heated at sixtydegrees Celsius for 16 hours. The solution was concentrated in vacuo andthe aqueous residue was acidified to pH=4.0. The resulting precipitatewas filtered to give the desired hydrochloride salt as a white solid(5.96 g, 80%). HRMS MH⁺ calculated for C₂₁H₂₂NSO₅F₃: 458.1249, found458.1260.

Part E: To a solution of the hydrochloride salt of part D (5.96 g, 12.0mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.96 g, 14.0mmol), N-methyl morpholine (3.9 mL, 36.0 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (2.11 g, 18.0 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.24 g,17.0 mmol). The solution was stirred at ambient temperature for 168hours. The insoluble material was removed by filtration and the filtratewas diluted with H₂O (400 mL) and extracted with ethyl acetate. Theorganic layer was washed with saturated NaCl and dried over MgSO₄,filtered and concentrated in vacuo. Chromatography on silica gel elutingwith 70% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (2.80 g, 41%).

Part F: To a solution of tetrahydropyranyl-protected hydroxamate of partE (2.8 g, 5.0 mmol) in dioxane (80 mL) was added 4 N HCl/dioxane (20mL). The reaction was stirred at ambient temperature for 5 hours, andthe solution was concentrated in vacuo. Trituration with diethyl etherafforded the title compound as a white solid (2.08 g, 84%). MS MH⁺calculated for C₂₁H₂₃N₂SO₅F₃: 473, found 473.

EXAMPLE 430 Preparation of1-ethyl-N-hydroxy-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (48 g, 115.0mmol) in ethyl acetate (750 mL) cooled to zero degrees Celsius wasbubbled gaseous HCl for 45 minutes. The reaction was stirred at thistemperature for 7 hours. The solution was concentrated in vacuo toafford a residue which was triturated with diethyl ether to afford thedesired hydrochloride salt as a white solid (32.8 g, 81%).

Part B: To a solution of the hydrochloride salt of part A (15.8 g, 45.0mmol) in DMF (75 mL) was added K₂CO₃ (12.4 g, 90 mmol) and bromoethane(3.4 mL, 45.0 mmol). The solution was stirred at ambient temperature for18 hours. The solution was diluted with H₂O (200 mL) and extracted withethyl acetate. The organic layer was washed with water, saturated NaCland dried over MgSO₄, filtered and concentrated in vacuo to afford thedesired ethyl amine as an oil (15.4 g, quantitative).

Part C: To a solution of ethyl amine of part B (5.2 g, 15.0 mmol) in DMF(50 mL) was added CsCO₃ (12.2 g, 37.5 mmol) and 4-isopropylphenol (3.15g, 23.0 mmol). The solution was stirred at ninety degrees Celsius for 5hours. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with water, saturated NaCland dried over MgSO₄, filtered and concentrated in vacuo. Chromatographyon silica gel eluting with 20% ethyl acetate/hexane provided the desireddiaryl ether as an oil (6.2 g, 95%). HRMS MH⁺ calculated forC₂₅H₃₃N₃SO₅: 460.2158, found: 460.2160.

Part D: To a solution of diaryl ether from part C (6.2 g, 13.0 mmol) inethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH(5.2 g, 130 mmol) in water (30 mL) and the solution was heated at sixtydegrees Celsius for 16 hours. The solution was concentrated in vacuo andthe aqueous residue was acidified to pH=4.0. The resulting precipitatewas filtered and washed with H₂O and diethyl ether to give desiredhydrochloride salt (6.0 g, quantitative). HRMS MH⁺ calculated forC₂₃H₂₉NSO₅: 432.1845, found 432.1859.

Part E: To a solution of the hydrochloride salt of part D (6.08 g, 13.0mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (2.11 g, 15.6mmol), N-methyl morpholine (4.3 mL, 39.0 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (2.28 g, 19.5 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.49 g,18.2 mmol). The solution was stirred at ambient temperature for 168hours. Insoluble material was removed by filtration and the filtrate wasdiluted with H₂O (400 mL) and extracted with ethyl acetate. The organiclayer was washed with saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo. Chromatography on silica gel eluting with 50%ethyl acetate/hexane provided the desired tetrahydropyranyl-protectedhydroxamate as a white solid (1.7 g, 25%). HRMS MH⁺ calculated forC₂₈H₃₈N₂SO₆: 531.2529, found 531.2537.

Part F: To a solution of tetrahydropyranyl-protected hydroxamate of partE (1.7 g, 3.0 mmol) in dioxane (60 mL) was added 4 N HCl/dioxane (10mL). The reaction was stirred at ambient temperature for 4 hours, andthe solution was concentrated in vacuo. Chromatography on C18 reversephase column eluting with acetonitrile/(HCl)water provided the titlecompound as a white solid (860 mg, 59%). HRMS MH⁺ calculated forC₂₃H₃₀N₂SO₅: 447.1954, found 447.1972.

EXAMPLE 431 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[4-(1-methylethyl)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 398, Part A (4.0 g, 10.2mmol) in DMF (40 mL) was added K₂CO₃ (12.46 g, 38.0 mmol) and4-isopropylphenol (4.99 g, 15.3 mmol). The solution was stirred atninety degrees Celsius for 24 hours. The solution was diluted with H₂O(400 mL) and extracted with ethyl acetate. The organic layer was washedwith water, saturated NaCl and dried over MgSO₄ filtered andconcentrated in vacuo. Chromatography on silica eluting with 30% ethylacetate/hexane provided the desired diaryl ether as a white solid (3.89g, 76%). HRMS MH⁺ calculated for C₂₆H₃₃NSO₅: 472.2158, found: 472.2171.

Part B: To a solution of diaryl ether from part A (3.89 g, 8.20 mmol) inethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH(3.30 g, 82.5 mmol) in water (25 mL) and the solution was heated atsixty degrees Celsius for 18 hours. The solution was concentrated invacuo to remove most of the organic solvents and the aqueous residue wasacidified to pH=3.0. The resulting precipitate was filtered and washedwith H₂O and ethyl ether to give desired hydrochloride salt (7.98 g,quantitative) as a white solid. MS MH⁺ calculated for C₂₄H₂₉NSO₅: 444,found: 444.

Part C: To a solution of the hydrochloride salt of part B (3.6 g, 7.0mmol) in DMF (70 mL) were added 1-hydroxybenzotriazole (1.22 g, 9.0mmol), N-methyl morpholine (2.3 mL, 21.0 mmol) and O-tetrahydropyranylhydroxyl amine hydrochloride (1.23 g, 10.5 mmol) followed by1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.01 g,10.4 mmol). The solution was stirred at ambient temperature for 15 days.The solution was diluted with H₂O (400 mL) and extracted with ethylacetate. The organic layer was washed with saturated NaCl and dried overMgSO₄, filtered and concentrated in vacuo. Chromatography on silica gel,eluting with 15% ethyl acetate/hexane, provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (3.51 g, 92%).HRMS MH⁺ calculated for C₂₉H₃₈N₂SO₆: 543.2529, found 543.2539.

Part D: To a solution of tetrahydropyranyl-protected hydroxamate of partC (3.51 g, 6.0 mmol) in methanol (10 mL) and dioxane (200 mL) was added4 N HCl/dioxane (30 mL). After stirring at ambient temperature for 2.5hours, the solution was concentrated in vacuo. Trituration with diethylether afforded the title compound as a white solid (2.56 g, 86%). MS MH⁺calculated for C₂₄H₃₀N₂SO₅: 459.1875, found 459.1978.

EXAMPLE 432 Preparation ofN-hydroxy-4-[[4-[4-(1-methylethoxy)phenoxy]phenyl]sulfonyl]-1-(1-methylethyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution ofethyl-4-[(4-fluorophenylsulfonyl)]-1-(1-methylethyl)-4-piperidinecarboxylate(2.0 g, 5.4 mmol) in N,N-dimethylformamide (10 mL) was added4-isopropyloxyphenol, which may be prepared according to the procedureof J. Indian Chem. Soc., 21, 1996, 507-511, (1.63 g, 10.7 mmol) andcesium carbonate (7 g, 21.5 mmol) and the resulting suspension washeated at 60 degrees Celsius for 16 hours. The reaction mixture was thenconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with 1 N sodium hydroxide, water and brine and dried overmagnesium sulfate. Concentration of the organic phase gave a residuewhich was purified by chromatography on silica gel eluting with ethylacetate/hexane to afford the desired aryl ether (1.06 g, 39%).

Part B: To a solution of the aryl ether (1.06 g, 2.1 mmol) in ethanol(20 mL) and water (20 mL) was added sodium hydroxide (0.84 g, 21 mmol)and the mixture was heated to 65 degrees Celsius for 16 hours. Thesolvents were then removed in vacuo. Water (50 mL) was added and themixture was again concentrated in vacuo and the resulting mixture wasacidified with 2 N HCl to pH=4-5. The solid precipitate was collected byfiltration and rinsed with diethyl ether to afford the desiredcarboxylic acid (3.13 g, 100%).

Part C: A solution of the carboxylic acid of part B (1.0 g, 2.0 mmol) inthionyl chloride (5 mL) was refluxed for 2 hours. The solvent wasremoved in vacuo. To the resulting residue in DMF (10 mL) was addedN-methyl morpholine (0.66 mL, 6.0 mmol)) and O-tetrahydropyranylhydroxyl amine hydrochloride (351 mg, 3.0 mmol). The solution wasstirred at ambient temperature for 18 hours. The suspension was filteredand the filtrate was diluted with H₂O (400 mL) and extracted with ethylacetate. The organic layer was washed with saturated NaCl and dried overMgSO₄, filtered and concentrated in vacuo. Chromatography on silica geleluting with 90% ethyl acetate/hexane provided the desiredtetrahydropyran-protected hydroxamate as a white solid (280 mg, 23%).HRMS MH⁺ calculated for C₂₉H₄₀N₂SO₇: 561.2634, found 561.2653.

Part D: To a solution of tetrahydropyranyl-protected hydroxamate of partC (275 mg, 0.48 mmol) in dioxane (15 mL) was added 4 N HCl/dioxane (5mL). After stirring at ambient temperature for 2 hours, the solution wasconcentrated in vacuo. Trituration with diethyl ether and filtration ofthe resulting solid gave the title compound as a white solid (193 mg,76%). MS MH⁺ calculated for C₂₄H₃₂N₂SO₆: 477, found 477.

EXAMPLE 433 Preparation of4-[[4-[(2-fluorophenyl)thio]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part D (6.0 g, 14.4mmol) in N,N-dimethylformamide (30 mL) were added 2-fluorothiophenol(2.22 g, 17.3 mmol) and potassium carbonate (2.40 g, 17.3 mmol), and theresulting suspension was stirred at ambient temperature for 48 hours.The reaction mixture was then diluted with ethyl acetate (200 mL) andwashed with 1 N sodium hydroxide (200 mL) and brine (3×). Concentrationof the organic phase afforded a residue that was purified bychromatography on silica gel, eluting with ethyl acetate/hexane (1:4),to afford the desired aryl sulfide (8.0 grams, 100%) as a white solid.

Part B: To a solution of the ethyl ester of part A (8.0 g, 15 mmol) inethanol (90 mL) and water (20 mL) was added sodium hydroxide (6.1 g, 152mmol), and the mixture was heated to 65 degrees Celsius for 16 hours.Volatile organics were removed in vacuo and the resulting aqueousmixture was acidified with 2 N HCl to pH=3-4. Solid sodium chloride wasadded and the mixture was extracted with ethyl acetate. The combinedorganic extracts were washed with brine and dried with magnesiumsulfate. Removal of the solvent afforded the desired carboxylic acid(4.92 g, 68%).

Part C: To a solution of the carboxylic acid of part B (4.92 g, 9.93mmol) in N,N-dimethylformamide (100 mL) were added 4-methylmorpholine(1.52 g, 15.0 mmol), N-hydroxybenzotriazole (1.62 g, 12.0 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.70 g,14.1 mmol), followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.24g, 15.0 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate (200 mL) and washed with water and brine. Concentrationand purification by chromatography on silica gel afforded the protectedhydroxamate derivative (4.9 mg, 83%).

Part D: Hydrogen chloride gas was bubbled for 10 minutes through an icebath-cooled solution of the protected hydroxamate of part C (4.9 g, 8.24mmol) in ethyl acetate (30 mL). The mixture was then allowed to stand atambient temperature for 2 hours, after which time the solvent wasremoved in vacuo. Fresh ethyl acetate (30 mL) was added and then removedin vacuo, and this procedure was repeated. Ethyl acetate (50 mL) wasthen added and the solid was collected by filtration to afford a solidthat was purified by reverse-phase chromatography, eluting withacetonitrile/water (gradient of 20/80 up to 100% acetonitrile), toafford the title compound (1.9 g, 43%). Analytical calculation forC₁₈H₁₉FN₂O₄S₂.HCl: C, 48.37; H, 4.51; N, 6.27; Cl, 7.93. Found: C,48.14; H, 4.33; N, 6.21; Cl, 8.64. HRMS (ESI) MH⁺ calculated forC₁₈H₁₉FN₂O₄S₂: 411.0849, found 411.0844.

EXAMPLE 434 Preparation of4-[[4-[(2-fluorophenyl)thio]phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part F (4.46 g, 12.6mmol) in N,N-dimethylformamide (30 mL) were added 2-fluorothiophenol(1.94 g, 15.1 mmol) and potassium carbonate (2.09 g, 15.1 mmol), and theresulting suspension was stirred at ambient temperature for 48 hours.The reaction mixture was then diluted with ethyl acetate (200 mL) andwashed with 1 N sodium hydroxide (200 mL) and brine (3×). Concentrationof the organic phase afforded the desired aryl sulfide (5.2 grams, 90%).

Part B: To a solution of the ethyl ester of part A (5.1 g, 11.4 mmol) inethanol (90 mL) and water (30 mL) was added sodium hydroxide (5.0 g, 125mmol), and the mixture was heated to 65 degrees Celsius for 16 hours.Organics were removed in vacuo and the resulting aqueous mixture wasacidified with 2 N HCl to pH=3-4. Solid sodium chloride was added andthe mixture was extracted with ethyl acetate. The combined organicextracts were washed with brine and dried with magnesium sulfate.Removal of the solvent afforded the desired carboxylic acid (4.5 g,94%).

Part C: To a solution of the carboxylic acid of part B (4.5 g, 11.0mmol) in N,N-dimethylformamide (50 mL) were added 4-methylmorpholine(1.62 g, 16.0 mmol), N-hydroxybenzotriazole (1.73 g, 12.8 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.87 g,14.9 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.39g, 16.0 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate (200 mL) and washed with water and brine. Concentrationand purification by chromatography on silica gel afforded the protectedhydroxamate derivative that was used directly in the next step.

Part D: Hydrogen chloride gas was bubbled for 10 minutes through an icebath-cooled solution of the protected hydroxamate of part C in ethylacetate (30 mL). The mixture was then allowed to stand at ambienttemperature for 2 hours after which time the solvent was removed invacuo. Fresh ethyl acetate (30 mL) was added and then removed in vacuo,and this procedure was repeated. Ethyl acetate (50 mL) was then addedand the solid was collected by filtration to afford a solid which waspurified by reverse-phase chromatography eluting with acetonitrile/water(gradient of 20/80 up to 100% acetonitrile) to afford the title compound(1.85 g, 35% for parts C and D). HRMS (ESI) MH⁺ calculated forC₂₁H₂₁FN₂O₄S₂: 449.1005, found 449.1023.

EXAMPLE 435 Preparation of4-[[4-(4-ethoxyphenoxy)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part F (8.00 g, 22.6mmol) in N,N-dimethylformamide (50 mL) were added 4-ethoxyphenol (9.38g, 70 mmol) and cesium carbonate (22.8 g, 70 mmol), and the resultingsuspension was heated at 75 degrees Celsius for 20 hours. The reactionmixture was then diluted with ethyl acetate (1000 mL) and washed with 1N sodium hydroxide, water and brine. Concentration of the organic phasegave a residue that was purified by chromatography on silica gel,eluting with ethyl acetate/hexane (1:2), to afford the desired diarylether (10.5 grams, 99%).

Part B: To a solution of the ethyl ester of part A (10.5 g, 22.3 mmol)in ethanol (70 mL) and water (60 mL) was added sodium hydroxide (8.9 g,222 mmol), and the mixture was heated to 65 degrees Celsius for 16hours. Volatile organics were removed in vacuo and the resulting aqueousmixture was acidified with 2 N HCl to pH=3-4. Solid sodium chloride wasadded and the mixture was extracted with ethyl acetate. The combinedorganic extracts were washed with brine and dried with magnesiumsulfate. Removal of the solvent afforded the desired carboxylic acid (10g, 100%).

Part C: To a solution of the carboxylic acid of part B (10 g, 22.5 mmol)in N,N-dimethylformamide (50 mL) were added 4-methylmorpholine (3.42 g,33.8 mmol), N-hydroxybenzotriazole (3.66 g, 27.1 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.05 g,31.6 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (5.05g, 33.8 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate (200 mL) and washed with water and brine. Concentrationand purification by chromatography on silica gel, eluting with ethylacetate/hexane (1:1), afforded the protected hydroxamate derivative (6.5g, 53%) which was used directly in the next step.

Part D: To a solution of the protected hydroxamate of part C inmethanol/1,4-dioxane (1:3, 70 mL) was added 4 N HCl/1,4-dioxane (30 mL)and the solution was stirred at ambient temperature for 4 hours. Thesolvent was then removed in vacuo. Methanol (40 mL) was added and thenremoved in vacuo. Diethyl ether (100 mL) was added and the resultingsolid was collected by filtration to afford the title compound (4.3 g,72%). Analytical calculation for C₂₃H₂₆N₂O₆S.HCl.H₂O: C, 53.85; H, 5.70;N, 5.46; Cl, 6.91; S, 6.25. Found: C, 53.65; H, 5.62; N, 5.41; Cl, 6.86;S, 6.48. MS (ESI) MH⁺ calculated for C₂₃H₂₆N₂O₆S: 459, found 459.

EXAMPLE 436 Preparation ofN-hydroxy-4-[[4-[4-(methylsulfonyl)phenoxy]phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part F (2.5 g, 6.4mmol) in N,N-dimethylformamide (15 mL) were added4-methylsulphonylphenol (3.5 g, 20.3 mmol) and cesium carbonate (8.7 g,27 mmol), and the resulting suspension was heated at 90 degrees Celsiusfor 16 hours. The reaction mixture was then concentrated in vacuo. Theresidue was dissolved in ethyl acetate (500 mL) and washed with 1 Nsodium hydroxide, water and brine. Concentration of the organic phasegave a residue which was purified by chromatography on silica geleluting with ethyl acetate/hexane (1:1) to afford the desired aryl ether(2.5 grams, 77%).

Part B: To a solution of the ethyl ester of part A (2.5 g, 4.9 mmol) inethanol (50 mL) and water (30 mL) was added sodium hydroxide (2.0 g, 49mmol) and the mixture was heated to 65 degrees Celsius for 8 hours. Thesolvents were removed in vacuo. Water (50 mL) was added, the mixture wasagain concentrated in vacuo and the resulting mixture was acidified with2 N HCl to pH=4-5. The solid precipitate was collected by filtration toafford the desired carboxylic acid (1.57 g, 67%).

Part C: To a solution of the carboxylic acid of part B (1.57 g, 3.3mmol) in N,N-dimethylformamide (15 mL) were added 4-methylmorpholine(0.5 g, 4.9 mmol), N-hydroxybenzotriazole (0.53 g, 3.9 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.88 g,4.6 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.74,4.9 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate (200 mL) and washed with water and brine. Concentrationand purification by chromatography on silica gel, eluting with ethylacetate/hexane, afforded the protected hydroxamate derivative (1.5 g,79%), which was used directly in the next step.

Part D: To a solution of the protected hydroxamate of part C (1.5 g,2.60 mmol) in methanol/1,4-dioxane (1:3, 40 mL) was added 4 NHCl/1,4-dioxane (10 mL), and the solution was stirred at ambienttemperature for 3 hours. The solvent was then removed in vacuo. Methanol(30 mL) was added and then removed in vacuo. Diethyl ether (100 mL) wasadded and the resulting solid was collected by filtration to afford thetitle compound (1.35 g, 98%). Analytical calculated forC₂₂H₂₄N₂O₇S₂.HCl: C, 49.95; H, 4.76; N, 5.30; Cl, 6.70; S, 12.12. Found:C, 49.78; H, 4.56; N, 5.25; Cl, 6.98; S, 11.98. HRMS (ESI) MH₊calculated for C₂₂H₂₄N₂O₇S₂: 493.1103, found 493.1116.

EXAMPLE 437 Preparation ofN-hydroxy-4-[[4-[(phenylmethyl)amino]phenyl]sulfonyl]-1-(2-propynyl-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 9, Part F (2.5 g, 6.4mmol) in N,N-dimethylformamide (30 mL) were added benzylamine (3.44 g,32.1 mmol) and cesium carbonate (10.5 g, 32.3 mmol) and the resultingsuspension was heated at 100 degrees Celsius for 16 hours. The reactionmixture was then concentrated in vacuo. The residue was dissolved inethyl acetate (500 mL) and washed with water and brine and dried overmagnesium sulfate. Concentration of the organic phase gave a residuethat was purified by chromatography on silica gel, eluting with ethylacetate/hexane (1:1), to afford the desired benzyl aniline derivative(2.5 grams, 88%).

Part B: To a solution of the ethyl ester of part A (2.5 g, 5.67 mmol) inethanol (50 mL) and water (30 mL) was added sodium hydroxide (2.27 g,56.7 mmol), and the mixture was heated to 65 degrees Celsius for 8hours. The solvents were removed in vacuo. Water (50 mL) was added andthe mixture was again concentrated in vacuo and the resulting mixturewas acidified with 2 N HCl to pH=4-5. The solid precipitate wascollected by filtration and rinsed with diethyl ether to afford thedesired carboxylic acid (2.3 g, 98%).

Part C: To a solution of the carboxylic acid of part B (2.3 g, 5.57mmol) in N,N-dimethylformamide (15 mL) were added 4-methylmorpholine(0.85 g, 8.36 mmol), N-hydroxybenzotriazole (0.9 g, 6.69 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.5 g,7.8 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.25,8.36 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue which was dissolved inethyl acetate and washed with water and brine. Concentration andpurification by chromatography on silica gel, eluting with ethylacetate/hexane, afforded the protected hydroxamate derivative which wasused directly in the next step.

Part D: Hydrogen chloride gas was bubbled for 10 minutes through an icebath-cooled solution of the protected hydroxamate of part C in ethylacetate (50 mL). The solvent was then removed in vacuo. Ethyl acetate(100 mL) was added and then removed in vacuo. Ethyl acetate (100 mL) wasthen added and the resulting solid was collected by filtration to affordthe title compound (1.6 g, 62% for steps C and D). HRMS (ESI) MH⁺calculated for C₂₂H₂₅N₃O₄S: 428.1644, found 428.1652.

EXAMPLE 438 Preparation of1-ethyl-N-hydroxy-4-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 429, Part B (1.0 g, 2.9mmol) in N,N-dimethylacetamide (30 mL) were added4-(trifluoromethyl)benzyl alcohol (1.53 g, 8.74 mmol) and cesiumcarbonate (2.85 g, 8.74 mmol), and the resulting suspension was heatedat 95-100 degrees Celsius for 8 hours. The reaction mixture was thenconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with 1 N sodium hydroxide, water and brine. Concentration of theorganic phase gave a residue that was purified by chromatography onsilica gel eluting with ethyl acetate/hexane to afford the desired arylether (0.8 grams, 54%).

Part B: To a solution of the ethyl ester of part A (0.8 g, 1.5 mmol) inethanol (50 mL) and water (50 mL) was added sodium hydroxide (1.0 g, 25mmol) and the mixture was heated to 60 degrees Celsius for 16 hours. Thesolvents were removed in vacuo. Water (50 mL) was added and the mixturewas acidified with 2 N HCl to pH=4. The solid precipitate was collectedby filtration to afford the desired carboxylic acid (0.75 g, 99%).

Part C: To a solution of the carboxylic acid of part B (0.75 g, 1.54mmol) in N,N-dimethylformamide (10 mL) were added 4-methylmorpholine(0.47 g, 4.6 mmol), N-hydroxybenzotriazole (0.25 g, 1.85 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.41 g,2.16 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.35,2.3 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate (200 mL) and washed with water and brine. Concentrationand purification by chromatography on silica gel, eluting with ethylacetate/hexane, afforded the protected hydroxamate derivative (250 mg,57%).

Part D: To a solution of the protected hydroxamate of part C (250 mg,0.43 mmol) in methanol/1,4-dioxane (1:3, 20 mL) was added 4 NHCl/1,4-dioxane (5 mL) and the solution was stirred at ambienttemperature for 3 hours. The solvent was then removed in vacuo. Anadditional portion of ethyl acetate was added and then removed in vacuo.Diethyl ether (100 mL) was added and the resulting solid was collectedby filtration to afford the title compound (190 mg, 82%). MS (CI) MH⁺calculated for C₂₂H₂₅F₃N₂O₅S: 487, found 487.

EXAMPLE 439 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[4-(1-methylethoxy)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of Example 398, Part A (2.49 g, 7.0mmol) in N,N-dimethylacetamide (30 mL) were added 4-isopropoxyphenol,which may be prepared according to the procedure of J. Indian Chem. Soc.73, 1996, 507-511 (1.28 g, 8.4 mmol) and cesium carbonate (5.48 g, 16.8mmol), and the resulting suspension was heated at 60 degrees Celsius for16 hours. The reaction mixture was then concentrated in vacuo. Theresidue was dissolved in ethyl acetate and washed with 1 N sodiumhydroxide, water and brine. Concentration of the organic phase gave aresidue which was purified by chromatography on silica gel, eluting withethyl acetate/hexane, to afford the desired aryl ether (2.8 grams, 82%).

Part B: To a solution of the ethyl ester of part A (2.8 g, 5.7 mmol) inethanol (50 mL) and water (50 mL) was added sodium hydroxide (2.3 g, 57mmol) and the mixture was heated to 60 degrees Celsius for 16 hours. Thesolvents were removed in vacuo. Water (50 mL) was added and the mixturewas acidified with 2 N HCl to pH=4. The solid precipitate was collectedby filtration to afford the desired carboxylic acid (1.4 g, 53%).

Part C: To a solution of the carboxylic acid of part B (1.4 g, 3.1 mmol)in N,N-dimethylformamide (15 mL) were added 4-methylmorpholine (0.92 g,9.1 mmol), N-hydroxybenzotriazole (0.49 g, 3.66 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.82 g,4.26 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.68g, 4.5 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate and washed with water and brine. Concentration andpurification by chromatography on silica gel, eluting with ethylacetate/hexane, afforded the protected hydroxamate derivative which wasused directly in the next step.

Part D: To a solution of the protected hydroxamate from part C inmethanol/1,4-dioxane (1:3, 20 mL) was added 4 N HCl/1,4-dioxane (10 mL)and the solution was stirred at ambient temperature for 3 hours. Thesolvent was then removed in vacuo. An additional portion of ethylacetate was added and then removed in vacuo. Diethyl ether was added andthe resulting solid was collected by filtration to afford the titlecompound (0.3 g, 19% for parts C and D together). Analytical calculationfor C₂₄H₃₀N₂O₆S.HCl: C, 56.41; H, 6.11; N, 5.48. Found: C, 56.04; H,5.82; N, 5.44. MS (CI) MH⁺ calculated for C₂₄H₃₀N₂O₆S: 475, found 475.

EXAMPLE 440 Preparation of4-[[4-[[2-(4-chlorophenyl)-ethyl]amino]phenyl]sulfonyl]-1-ethyl-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution of the product of 10 Example 429, Part B (1.0 g,2.91 mmol) in N,N-dimethylacetamide (20 mL) were added4-chlorophenethylamine (0.91 g, 5.8 mmol) and cesium carbonate (3.80 g,11.6 mmol), and the resulting suspension was heated at 90 degreesCelsius for 24 hours. The reaction mixture was then concentrated invacuo. The residue was dissolved in ethyl acetate and washed with 1 Nsodium hydroxide, water and brine. Concentration of the organic phasegave a residue which was purified by chromatography on silica geleluting with ethyl acetate/hexane to afford the desired aryl ether (0.8grams, 58%).

Part B: To a solution of the ethyl ester of part A (0.8 g, 1.7 mmol) inethanol (50 mL) and water (50 mL) was added sodium hydroxide (1.0 g, 25mmol), and the mixture was heated to 60 degrees Celsius for 16 hours.The solvents were removed in vacuo. Water (50 mL) was added and themixture was acidified with 2 N HCl to pH=4. The solid precipitate wascollected by filtration to afford the desired carboxylic acid (0.75 g,92%).

Part C: To a solution of the carboxylic acid of part B (0.75 g, 1.7mmol) in N,N-dimethylformamide (20 mL) were added 4-methylmorpholine(0.51 g, 5.1 mmol), N-hydroxybenzotriazole (0.27 g, 2.0 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.45 g,2.3 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.37 g,2.5 mmol). After stirring for 16 hours at ambient temperature thereaction mixture was concentrated to a residue which was dissolved inethyl acetate and washed with water and brine. Concentration andpurification by chromatography on silica gel, eluting with ethylacetate/hexane, afforded the protected hydroxamate derivative which wasused directly in the next step.

Part D: To a solution of the protected hydroxamate from part C inmethanol/1,4-dioxane was added 4 N HCl/1,4-dioxane (10 mL) and thesolution was stirred at ambient temperature for 3 hours. The solvent wasthen removed in vacuo. An additional portion of ethyl acetate was addedand then removed in vacuo. Diethyl ether was added and the resultingsolid was collected by filtration to afford the title compound (30 mg,4% for parts C and D together).

EXAMPLE 441 Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[[[4-(trifluoromethoxy)phenyl]methyl]amino]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution ofethyl-4-[(4-fluorophenylsulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(1.38 g, 3.7 mmol) in N,N-dimethylformamide (20 mL) were added4-(trifluoromethyloxy)benzylamine (1.0 g, 5.2 mmol) and cesium carbonate(1.7 g, 5.2 mmol), and the resulting suspension was heated at 90 degreesCelsius for 24 hours. The reaction mixture was then concentrated invacuo. The residue was dissolved in ethyl acetate and washed with 1 Nsodium hydroxide, water and brine. Concentration of the organic phasegave a residue that was purified by chromatography on silica gel,eluting with ethyl acetate/hexane, to afford the desiredtrifluoromethoxy compound (0.6 grams, 30%).

Part B: To a solution of the ethyl ester of part A (0.6 g, 1.1 mmol) inethanol (30 mL), water (30 mL) and tetrahydrofuran (15 mL) was addedsodium hydroxide (0.44 g, 11 mmol), and the mixture was heated to 60degrees Celsius for 16 hours. The solvents were removed in vacuo water(50 mL) was added and the mixture was acidified with 2 N HCl to pH=4.The solid precipitate was collected by filtration to afford the desiredcarboxylic acid (0.5 g, 88%).

Part C: To a solution of the carboxylic acid of part B (0.50 g, 0.98mmol) in N,N-dimethylformamide (10 mL) were added 4-methylmorpholine(0.15 g, 1.5 mmol), N-hydroxybenzotriazole (0.16 g, 1.2 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.27 g,1.4 mmol) followed by O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.22 g,1.5 mmol). After stirring for 16 hours at ambient temperature, thereaction mixture was concentrated to a residue that was dissolved inethyl acetate and washed with water and brine. Concentration andpurification by chromatography on silica gel, eluting with ethylacetate/hexane, afforded the protected hydroxamate derivative (110 mg,18%).

Part D: To a solution of the protected hydroxamate from part C (110 mg,0.18 mmol) in methanol/1,4-dioxane (1:4, 20 mL) was added 4 NHCl/1,4-dioxane (7 mL) and the solution was stirred at ambienttemperature for 3 hours. The solvent was then removed in vacuo. Anadditional portion of methanol (20 mL) was added and then removed invacuo. Diethyl ether was added and the resulting solid was collected byfiltration to afford the title compound (30 mg, 31%). MS (ESI) MH⁺calculated for C₂₃H₂₈F₃N₃O₆S: 532, found 532.

EXAMPLE 442 Preparation ofN-hydroxy-4-[[4-[4-(1-methylethoxy)phenoxy]phenyl]sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxamide,monohydrochloride

Part A: To a solution ofethyl-4-[(4-fluorophenyl-sulfonyl)]-1-(2-methoxyethyl)-4-piperidinecarboxylate(2.0 g, 5.4 mmol) in N,N-dimethylformamide (20 mL) were added4-isopropoxyphenol, which can be prepared according to the procedure ofJ. Indian Chem. Soc. 73, 1996, 507-511 (1.63 g, 10.7 mmol) and cesiumcarbonate (7 g, 21.5 mmol), and the resulting suspension was heated at60 degrees Celsius for 16 hours. The reaction mixture was thenconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with 1 N sodium hydroxide, water and brine and dried overmagnesium sulfate. Concentration of the organic phase gave a residuethat was purified by chromatography on silica gel, eluting with ethylacetate/hexane, to afford the desired aryl ether (1.37 grams, 50%).

Part B: To a solution of the ethyl ester of part A (1.37 g, 2.7 mmol) inethanol (30 mL) and water (30 mL) was added sodium hydroxide (1.08 g, 27mmol), and the mixture was heated to 65 degrees Celsius for 16 hours.The solvents were then removed in vacuo. Water (50 mL) was added and themixture was again concentrated in vacuo and the resulting mixture wasacidified with 2 N HCl to pH=4-5. The solid precipitate was collected byfiltration and rinsed with diethyl ether to afford the desiredcarboxylic acid (1.25 g, 100%).

Part C: To a suspension of the carboxylic acid of part B (1.25 g, 2.7mmol) in N,N-dimethylformamide (15 mL) were added 4-methylmorpholine(0.82 g, 8.1 mmol), O-(tetrahydro/2H-pyran-2-yl)hydroxylamine (0.61, 4.1mmol) followed by bromo-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBroP, 1.51 g, 3.3 mmol). After stirring for 16 hours at ambienttemperature, the reaction mixture was concentrated to a residue that wasdissolved in ethyl acetate and washed with water and brine.Concentration and purification by chromatography on silica, gel elutingwith ethyl acetate/hexane, afforded the protected hydroxamate derivative(1.0 g, 63%).

Part D: Hydrogen chloride gas was bubbled for 5 minutes through an icebath-cooled solution of the protected hydroxamate of part C (1.0 g, 1.7mmol) in ethyl acetate (20 mL). After stirring at ambient temperaturefor 5 hours, the solvent was removed in vacuo. Ethyl acetate (30 mL) wasadded and then removed in vacuo. Ethyl acetate (30 mL) was again addedand the resulting solid was collected by filtration to afford the titlecompound (0.5 g, 56%). Analytical calculation forC₂₄H₃₂N₂O₇S.HCl.1.5H₂O: C, 51.84; H, 6.53; N, 5.04; Cl, 6.38; S, 5.77.Found: C, 51.87; H, 6.12; N, 4.92; Cl, 6.38; S, 5.84. MS MH⁺ calculatedfor C₂₄H₃₂N₂O₇S: 493, found 493.

EXAMPLE 443 Preparation ofN-Hydroxy-1-(2-pyridinylmethyl)-4-[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

Part A: The aryl flouride from Example 9, Part D (6.22 g, 15 mmol) wascombined with powdered potassium carbonate (3.04 g, 22 mmol),4-(trifluoromethoxy)phenol (3.92 g, 322 mmol), and N,N-dimethylforamide(7 mL), and the mixture was stirred at ninety degrees Celsius forsixteen hours. Additional 4-(trifluoromethoxy)-phenol (1 g) andpotassium carbonate (800 mg) were added and the reaction was continuedat one hundred and fifteen degrees Celsius for twenty additional hours.The mixture was diluted with water (100 mL) and extracted with ethylacetate (100 mL, then 2×25 mL). The combined organic layers were driedusing magnesium sulfate, concentrated, and chromatographed, affordingthe desired aryl ether as an oil (9.6 g, about quantitative).

Part B: The aryl ether from part A (9.6 g, about 15 mmol) was dissolvedin ethyl acetate (45 mL). A solution of HCl in dioxane (4N, 12 mL) wasadded, and the mixture was stirred at ambient temperature for threehours. Thin layer chromatography indicated incomplete deprotection.Concentrated aqueous HCl (4 mL) was added and the reaction was heated toreflux with a heat gun several times. The solution was concentrated andwas then azeotroped with acetonitrile to afford the desired piperidinehydrochloride salt as a foam (9.6 g). Nuclear magnetic resonancespectroscopy indicated some contaminating 4-(trifluoromethoxy)phenol,which must have been carried through from part A.

The piperidine hydrochloride salt (6.0 g) was dissolved in ethyl acetate(125 mL) and washed with aqueous sodium hydroxide (2 g NaOH in 50 mLwater). The organic layer was dried with magnesium sulfate and filteredthrough a pad of silica gel. The phenol contaminant was eluted. Thedesired piperidine was then freed from the filter cake by elution withmethanol containing 1% aqueous ammonium hydroxide (circa 100 mL). Thefiltrate was concentrated and azeotroped with acetonitrile to yield 3.3g (7.3 mmol).

Part C: The piperidine from Part B (1.24 g, 2.7 mmol) was combined withpowdered potassium carbonate (828 mg, 6.0 mmol), 2-picolyl hydrochloride(492 mg, 3.0 mmol), and N,N-dimethylformamide (3 mL), and the mixturewas stirred at ambient temperature for two hours, then heated at fiftydegrees Celsius for two additional hours. The mixture was diluted withwater (40 mL) and extracted with ethyl acetate (150 mL, then 50 mL). Thecombined organic layers were dried using magnesium sulfate,concentrated, and chromatographed, affording the desired ester as an oil(1.13 g, 74%).

Part D: The ester from part C (1.1 g, 2.0 mmol) was combined withethanol (6 mL), water (2 mL), and potassium hydroxide (0.90 g, 16 mmol).The mixture was brought to reflux and heated for four and one-halfhours. The solution was then cooled to zero degrees Celsius andacidified using concentrated aqueous hydrogen chloride. The solvent wasremoved, and the resulting solids were dried by azeotroping withacetonitrile. A vacuum was applied until constant weight was achieved.

The crude acid hydrochloride salt was stirred with N-methylmorpholine(about 0.5 mL), 1-hydroxybenzotriazole (0.405 g, 3 mmol),O-tetrahydropyranyl hydroxylamine (0.35 g, 3.0 mmol), andN,N-dimethyformamide (9 mL). After ten minutes,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.57 g, 3.0mmol) was added, and the mixture was stirred overnight. The reaction wasthen diluted with half-saturated aqueous sodium bicarbonate (50 mL), andextracted with ethyl acetate (100 mL, then 25 mL). The combined organiclayers were dried over magnesium sulfate, concentrated, andchromatographed (9:1 ethyl acetate:methanol) to afford the desiredtetrahydropyranyl-protected hydroxamate as a yellow oil (1.20 g, 95%).

Part E: The tetrahydropyranyl-protected hydroxamate (1.20 g, 1.90 mmol)was diluted with methanol (9 mL). Acetyl chloride (0.78 mL, 11 mmol) wasadded over two minutes. The reaction was stirred for 2 hours at ambienttemperature, then concentrated to afford the desired dihydrochloridesalt (1.20 g, quantitative yield) as a white crystalline solid.Analytical calculation for C₂₅H₂₄F₃N₃O₆S.2HCl.1/3H₂O: C, 47.58; H, 4.07;N, 6.66. Found: C, 47.31; H, 4.14; N, 6.80.

EXAMPLE 444 In Vitro Metalloprotease Inhibition

The compounds prepared in the manner described in the Examples abovewere assayed for activity by an in vitro assay. Following the proceduresof Knight et al., FEBS Lett. 296(3):263 (1992). Briefly,4-aminophenylmercuric acetate (APMA) or trypsin-activated MMPs wereincubated with various concentrations of the inhibitor compound at roomtemperature for 5 minutes.

More specifically, recombinant human MMP-13, MMP-1, MMP-2 and MMP-9enzymes were prepared in laboratories of the assignee following usuallaboratory procedures. MMP-13 from a full length cDNA clone wasexpressed as a proenzyme using a baculovirus as discussed in V. A.Luckow, Insect Cell Expression Technology, pages 183-218, in ProteinEngineering: Principles and Practice, J. L. Cleland et al eds.,Wiley-Liss, Inc., (1996). See, also, Luckow et al., J. Virol.,67:4566-4579 (1993); O'Reilly et al., Baculovirus Expression Vectors: ALaboratory Manual, W.H. Freeman and Company, New York, (1992); and Kinget al., The Baculovirus Expression System: A Laboratory Guide, Chapman &Hall, London (1992) for further details on use of baculovirus expressionsystems. The expressed enzyme was purified first over a heparin agarosecolumn and then over a chelating zinc chloride column. The proenzyme wasactivated by APMA for use in the assay.

MMP-1 expressed in transfected HT-1080 cells was provided by Dr. HaroldWelgus of Washington University, St. Louis, Mo. The enzyme was alsoactivated using APMA and was then purified over a hydroxamic acidcolumn. Dr. Welgus also provided transfected HT-1080 cells thatexpressed MMP-9. Transfected cells that expressed MMP-2 were provided byDr. Gregory Goldberg, also of Washington University. Studies carried outusing MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in thetable below with an asterisk. Further specifics for preparation and useof these enzymes can be found in the scientific literature describingthese enzymes. See, for example, Enzyme Nomenclature, Academic Press,San Diego, Calif. (1992) and the citations therein, and Frije et al., J.Riol. Chem., 26(24): 16766-16773 (1994). The enzyme substrate is amethoxycoumarin-containing polypeptide having the following sequence:

MCA-ProLeuGlyLeuDpaAlaArgNH₂, wherein MCA is methoxycoumarin and Dpa is3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate iscommercially available from Baychem as product M-1895.

The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mMCaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl ether at a pHvalue of 7.5. Assays were carried out at room temperature, and dimethylsulfoxide (DMSO) at a final concentration of 1 percent was used todissolve inhibitor compound.

The assayed inhibitor compound in DMSO/buffer solution was compared toan equal amount of DMSO/buffer with no inhibitor as control usingMicrofluor™ White Plates (Dynatech). The inhibitor or control solutionwas maintained in the plate for 10 minutes and the substrate was addedto provide a final concentration of 4 μM.

In the absence of inhibitor activity, a fluorogenic peptide was cleavedat the gly-leu peptide bond, separating the highly fluorogenic peptidefrom a 2,4-dinitrophenyl quencher, resulting in an increase offluorescence intensity (excitation at 328 nm/emission at 415 nm).Inhibition was measured as a reduction in fluorescent intensity as afunction of inhibitor concentration, using a Perkin Elmer L550 platereader. The IC₅₀ values were calculated from those values. The resultsare set fourth in the Inhibition Tables A and B below, reported in termsof IC₅₀ to three significant figures, where appropriate.

Inhibition Table A (nM) Example MMP-13 MMP-2 MMP-1 MMP-9 Number IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1 5.1 2.6 6600 31.6 2 0.25 0.1 2201.4 3 0.3 0.2 1140 4 0.35 0.23 1090 5 5 4800 1800 >10000 6 0.25 0.15 3277 37.2 1.8 >10000 235 8 24.1 4 >10000 290 9 0.5 0.2 9000 1.5 10 0.4 0.21600 0.3 11 6 4.4 >10000 12 <0.1 <0.1 464 13 0.6 0.4 >10000 8 14 0.1<0.1 464 15 0.4 0.2 3600 0.2 16 2.4 100 >10000 2500 17 0.3 0.2 400 0.318 0.5 0.3 800 19 9 13.9 >10000 20 1.7 23.5 10000 21 0.6 1.3 >10000 221.2 0.9 >10000 23 0.2 <0.1 2275 24 0.4 1 >10000 3.7 25 3 2.6 >10000 260.5 0.2 7700 7 27 0.45 0.4 >10000 4 28 <0.1 <0.1 770 29 0.3 0.15 >10,000

Inhibition Table B (nM) Example MMP-1 MMP-2 MMP-9 MMP-13 Number IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 30 350 0.1 0.3 0.1 31 370 <0.1 0.232 >10000 0.1 2.5 0.2 33 >10000 0.5 9.4 0.8 34 >10000 1.1 1.2 35 >100000.3 3 0.5 36 7300 0.4 8 0.6 37 1000 0.2 0.3 38 >10000 20 135 2239 >10000 230 24.5 40 4400 0.4 2.4 1.9 41 1200 0.15 0.2 42 2200 0.2 1.30.4 43 7000 0.4 0.8 44a >10000 <0.1 0.2 44b >10000 8000 >10000 45 88002.5 1.7 46 710000 — — 710000 47a >10000 7 14.6 47b >10000 3000 3100 48210 0.2 0.25 49 >10000 76.9 90.0 51 5500 0.7 1.3 52 >10000 2.7 5.953 >10000 0.3 92 1.5 54 >10000 60 120 55 1200 0.1 0.3 56 1500 <0.1 0.1557 1200 <0.1 0.2 58 >10000 83 30 59 >10000 130 180 60 >10000 64 14761 >10000 1500 2000 62 >10000 >10000 >10000 63 >10000 18.1 530 1.5 641470 <0.1 0.15 65 8000 0.6 4.4 0.7 66 >10000 4590 36000 67 1600 239 26868 >10000 5.3 130 6 69 1140 <0.1 0.2 <0.1 70 1500 0.2 7.3 0.8 71 36000.35 5 0.8 72 2100 <0.1 0.3 73 1140 <0.1 0.2 <0.1 74 >10000 130 48075 >10000 60 900 78 >10000 6 50 10 79 >10000 1 1.7 80 3000 0.1 1.8 0.281 3300 0.1 0.3 82 4000 0.1 0.3 83 8000 1.2 5 1.5 84 8000 1.8 2.5 85 500<0.1 0.4 <0.1 86 >10000 2.5 3.5 87 7200 0.8 13.9 0.35 88 1100 0.2 0.50.2 89 1200 0.15 0.4 0.25 90 1200 0.1 0.1 91 1800 1.5 40 2.1 92 >100001800 2430 93 8000 0.4 3.5 0.7 94 268 <0.1 0.4 <0.1 95 >10000 1 3.6 0.596 5000 0.2 1.3 0.3 97 4000 8.2 16.7 98 >10000 37 23.4 99 >10000 0.4 1100 435 <0.1 0.3 0.15 101 1800 0.3 2.9 0.45 102 2000 <0.1 0.2 103 >100000.8 10 0.7 104 >10000 1.5 42.8 0.65 105 >10000 3500 114 0.85 106 >1000027.1 12.1 107 >10000 12.1 6 108 2000 0.4 0.4 109 500 0.1 0.7 0.3 1102700 0.4 10 0.5 111 3700 0.5 1.3 112 1000 7 3.2 113 >10000 0.9 4 1143000 0.65 31.6 0.4 115 4500 0.3 31.6 0.6 116 2350 2 15.3 5.5 117 37000.6 45.4 4.8 118 2850 0.3 50 0.8 119 >10000 1.5 30 1.7 120 4000 0.4 0.4121 1200 <0.1 0.2 122 600 0.1 0.15 123 3600 1.8 27.8 1.8 124 1000 0.51.1 125 >10000 0.4 7 0.5 126 8000 11.3 10 127 >10000 37 40 128 >1000023.8 20 129 >10000 >100 1000 130 >10000 57.7 45.9 131 >10000 650 10132 >10000 420 133 >10000 90 27 134 9000 29 4 135 >10000 500 65136 >10000 445 40 137 >10000 300 34.7 138 >10000 >100 >100 139 >100001000 25.4 140 >10000 1000 60 141 >10000 >100 >100 142 >10000 600 70143 >10000 900 23.9 144 >10000 800 30.7 145 >10000 >100 >100 146 >10000650 32.6 147 >10000 2700 31 148 >10000 2400 31 149 >10000 1600 15.5150 >10000 1300 14.5 151 >10000 1500 35 152 >10000 2400 16.5 153 >100002700 13.5 154 >10000 1600 27 155 >10000 >1000 >100 156 >10000 3300 27.8157 >10000 6000 90 158 >10000 5000 80 159 >10000 2500 15.6 160 >100004700 33.7 161 >10000 >1000 >100 162 >10000 >1000 >100 163 >10000 400077.4 164 >10000 1750 20 165 >10000 330 13.6 166 >10000 >1000 >100167 >10000 >1000 >100 168 >10000 >1000 >100 169 10000 >1000 >100 17010000 >1000 >100 171 >10000 >1000 >100 172 >10000 >1000 >100173 >10000 >1000 >100 174 8000 900 >100 175 10000 >1000 >100 176 >10000400 25 177 >10000 400 21 178 >10000 540 >100 179 >10000 440 100 180 5000128 4 181 10000 121 6.1 182 >10000 240 4 183 >10000 288 40 184 >10000 947 185 >10000 210 17.5 186 >10000 120 10 187 >10000 290 12.1 188 >10000350 9.4 189 3700 94 8 190 >10000 220 10.6 191 >10000 350 4 192 >10000330 10 193 >10000 390 6 194 10000 165 8 195 10000 100 14.5 196 >10000240 25 197 7000 145 8 198 >10000 270 14.5 199 >10000 155 1.4 200 >1000024 17.5 201 >10000 22.4 13.6 202 >10000 54 9.15 203 8500 31 30204 >10000 25 27.1 205 7300 12.7 2 206 >10000 >10.0 20 207 >10000 30.628 208 >10000 27 27 209 >10000 19 20 210 >10000 27 20 211 >10000 33 24212 >10000 33 20 213 310 <1.0 <1.0 214 1100 <1.0 <1.0 215 250 <1.0 <1.0216 1000 <1 <1.0 217 600 <1.0 <1.0 218 >10000 <1.0 <1.0 219 >10000 <1.0<1.0 220 145 <1.0 <1.0 221 1600 <1.0 <1.0 222 100 <1.0 <1.0 223 1100<1.0 <1.0 224 >10000 18.1 16.7 225 >10000 54 70 226 >10000 18.6 6227 >10000 <1 <1 228 600 <1.0 <1.0 229 >10000 <1 <1 230 >10000 >100 >100231 650 <1.0 <1.0 232 <100 <1.0 <1.0

EXAMPLE 445 In Vivo Angiogenesis Assay

The study of angiogenesis depends on a reliable and reproducible modelfor the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, July1996, Vol. 37, No. 8.

In this assay, uniformly sized Hydron™ pellets containing bFGF andsucralfate were prepared and surgically implanted into the stroma mousecornea adjacent to the temporal limbus. The pellets were formed bymaking a suspension of 20 mL sterile saline containing 10 μg recombinantbFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol.The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh were separated to release thepellets.

The corneal pocket is made by anesthetizing a 7 week old C57B1/6 femalemouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length is performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket is dissected toward the temporallimbus. The pocket is extended to within 1.0 mm of the temporal limbus.A single pellet was placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet was then advanced to thetemporal end of the pocket. Antibiotic ointment was then applied to theeye.

Mice were dosed on a daily basis for the duration of the assay. Dosingof the animals was based on bioavailability and overall potency of thecompound an exemplary dose was 10 or 50 mg/kg (mpk) bid, po.Neovascularization of the corneal stroma begins at about day three andwas permitted to continue under the influence of the assayed compounduntil day five. At day five, the degree of angiogenic inhibition wasscored by viewing the neovascular progression with a slit lampmicroscope.

The mice were anesthetized and the studied eye was once again proptosed.The maximum vessel length of neovascularization, extending from thelimbal vascular plexus toward the pellet was measured. In addition, thecontiguous circumferential zone of neovascularization was measured asclock hours, where 30 degrees of arc equals one clock hour. The area ofangiogenesis was calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad{hours} \times 3.14 \times {vessel}\quad{{length}\left( {{in}\quad{mm}} \right)}} \right)}{2}$

Five to six mice were utilized for each compound in each study. Thestudied mice were thereafter compared to control mice and the differencein the area of neovascularization was recorded as an averaged value.Each group of mice so studied constitutes an “n” value of one, so that“n” values greater than one represent multiple studies whose averagedresult is provided in the table. A contemplated compound typicallyexhibits about 25 to about 75 percent inhibition, whereas the vehiclecontrol exhibits zero percent inhibition.

Data for four compounds of the above examples are provided below atdosages of 10 and 50 mpk.

Inhibition of Angiogenesis Dosage Example 10 mpk 50 mpk Marimastat — 48(n = 6)  4 18 (n = 3) 41 (n = 6)  9 50 (n = 2) 46 (n = 3) 10 47 (n = 1)54 (n = 2) 24 53 (n = 1) 78 (n = 1)

EXAMPLE 446 In Vivo PC-3 Tumor Reduction

PC-3 human pancreatic cancer cells (ATCC CRL 1435) were grown to 90%confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells weremechanically harvested using a rubber scraper, and then washed twicewith cold medium. The resulting cells were resuspended in cold mediumwith 30% matrigel (Collaborative Research) and the cell-containingmedium was maintained on ice until used.

Balb/c nu/nu mice at 7-9 weeks of age were anesthetized with avertin[2,2,2-tribromethanol/tamyl alcohol (1 g/1 mL) diluted 1:60 intophosphate-buffered sline] and 3-5×10⁶ of the above cells in 0.2 mL ofmedium were injected into the left flank of each mouse. Cells wereinjected in the morning, whereas dosing with aninhibitor began at 6 PM.The animals were gavaged BID from day zero (cell injection day) to day25-30, at which time the animals were euthanized and tumors weighed.

Compounds were dosed at 10 mg/mL in 0.5% methylcellulose/0.1%polysorbate 80 to provide a 50 mg/kg (mpk) dose twice each day, ordiluted to provide a 10 mg/kg (mpk) dose twice each day. Tumormeasurements began on day 7 and continued every third or fourth dayuntil completion of the study. Groups of ten mice were used in eachstudy and nine to ten survived. Each group of mice so studiedconstitutes an “n” value of one, so that “n” values greater than onerepresent multiple studies whose averaged result is provided in thetable. The results of this study for several of the before discussedcompounds are shown below as average reductions in tumor weight.

Average Percentage Reduction In Tumor Weight Dosage Example 10 mpk 50mpk Marimastat <5 39 (n = 2) 4 33 (n = 2) 43 (n = 2) 9 40 (n = 1) 60 (n= 1) 10  nt 59 (n = 1)

EXAMPLE 447 Tumor Necrosis Factor Assays

Cell Culture.

The cells used in the assay are the human moncytic line U-937 (ATCCCRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement(R-10) and are not permitted to overgrow. The assay is carried out asfollows:

1. Count, then harvest cells by centrifugation. Resuspend the pellet inR-10 supplement to a concentration of 1.540×10⁶ cells/mL.

2. Add test compound in 65 uL R-10 to the appropriate wells of a 96-wellflat bottom tissue culture plate. The initial dilution from a DMSO stock(100 mM compound) provides a 400 uM solution, from which five additionalthree-fold serial dilutions are made. Each dilution of 65 ul (intriplicate) yields final compound test concentrations of 100 μM, 33.3μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM.

3. The counted, washed and resuspended cells (200,000 cells/well) in 130μL are added to the wells.

4. Incubation is for 45 minutes to one hour at 37° C. in 5% CO₂ in awater saturated container.

5. R-10 (65 uL)containing 160 ng/mL PMA (Sigma) is added to each well.

6. The test system is incubated at 37° C. in 5% CO₂ overnight (18-20hours) under 100% humidity.

7. Supernatant, 150 μL, is carefully removed from each well for use inthe ELISA assay.

8. For toxicity, a 50 μL aliquot of working solution containing 5 mLR-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution CellProliferation Assay Cat. #G358/0,1 (Promega Biotech)] and 250 ul PMSsolution are added to each well containing the remaining supernatant andcells and the cells incubated at 37° C. in 5% CO₂ until the colordevelops. The system is excited at 570 nm and read at 630 nm.

TNF Receptor II ELISA Assay

1. Plate 100 μL/well 2 ug/mL mouse anti-human TNFrII antibody (R&DSystems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate.Incubate the plate at 4° C. overnight (about 18-20 hours).

2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween).

3. Add 200 μL 5% BSA in PBS and block at 37° C. in a water saturatedatmosphere for 2 hours.

4. Wash the plate with PBS-Tween.

5. Add sample and controls (100 ul of each) to each well. The standardsare 0, 50, 100, 200, 300 and 500 pg recombinant human TNFrII (R&DSystems #226-B2) in 100 μL 0.5% BSA in PBS. The assay is linear tobetween 400-500 pg of standard.

6. Incubate at 37° C. in a saturated atmosphere for 1.5 hours.

7. Wash the plate with PBS-Tween.

8. Add. 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&D Systems#AB226-PB in 0.5% BSA in PBS).

9. Incubate at 37° C. in a saturated atmosphere for 1 hour.

10. Wash the plate with PBS-Tween.

11. Add 100 μL anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS,Sigma #A5420).

11. Incubate at 37° C. in a saturated atmosphere for 1 hour.

12. Wash the plate with PBS-Tween.

13. Add 10 μL KPL TMB developer, develop at room temperature (usuallyabout 10 minutes), then terminate with phosphoric acid and excite at 450nm and read at 570 nm.

TNFα ELISA Assay

Coat Immulon® 2 plates with 0.1 mL/well of lug/mL Genzyme mAb in 0.1 MNaHCO₃ pH 8.0 buffer overnight (about 18-20 hours) at 4° C., wrappedtightly in Saran wrap.

Flick out coating solution and block plates with 0.3 mL/well blockingbuffer overnight at 4° C., wrapped in Saran wrap.

Wash wells thoroughly 4× with wash buffer and completely remove all washbuffer. Add 0.1 mL/well of either samples or rhTNFα standards. Dilutesamples if necessary in appropriate diluant (e.g. tissue culturemedium). Dilute standard in same diluant. Standards and samples shouldbe in triplicates.

Incubate at 37° C. for 1 hour in humified container.

Wash plates as above. Add 0.1 mL/well of 1:200 dilution of Genzymerabbit anti-hTNF.

Repeat incubation.

Repeat wash. Add 0.1 mL/well of 1 μg/mL Jackson goat anti-rabbit IgG(H+L)-peroxidase.

Incubate at 37° C. for 30 minutes.

Repeat wash. Add 0.1 mL/well of peroxide-ABTS solution.

Incubate at room temperature for 5-20 minutes.

Read OD at 405 nm.

12 Reagents are:

-   -   Genzyme mouse anti-human TNF? monoclonal (Cat. #80-3399-01)    -   Genzyme rabbit anti-human TNF? polyclonal (Cat. #IP-300)    -   Genzyme recombinant human TNF? (Cat. #TNF-H).    -   Jackson Immunoresearch peroxide-conjugated goat anti-rabbit IgG        (H+L) (Cat. #111-035-144).    -   Kirkegaard/Perry peroxide ABTS solution (Cat #50-66-01).    -   Immulon 2 96-well microtiter plates.    -   Blocking solution is 1 mg/mL gelatin in PBS with 1×thimerasol.    -   Wash buffer is 0.5 mL Tween 20 in 1 liter of PBS.        Results:

MTS TNFRII TNFα Toxicity Release Release Example TD₅₀ in IC₅₀ in IC₅₀ inNumber micromolar micromolar micromolar DMSO >100 >100 >1004 >100 >100 >50 6 >100 >100 >50 9 >100 >100 >50 10 >100 >100 >5013 >100 >100 >50 27 100 >100 >80 35 >100 >100 >80 69 100 >100 >8095 >100 >100 >50 379 80 >100 80

EXAMPLE 448 Pharmacokinetic (PK)-evaluation of MMP inhibitors in rats

Under metofane anesthesia, the femoral artery (all 8 rats) and femoralvein (only 4 of 8 rats) are isolated and canulated with PESO tubing andsecured with 3.0 silk suture. The following determinations require twocatheters, with the venous line being used for infusion of compound (inthe group of rats that receives compound via the intraveneous (IV)route.), and the arterial line being used for collection of bloodsamples. The rats are then placed in restraining cages that permitminimal movement and allowed to recover from anesthesia forapproximately 30 minutes. At time 0 (prior to dosing), blood samples(400 μL) are collected from arterial cannula.

One group of rats (4 rats per group) receives compound via the oralroute at a dosing volume of 2 mL/kg (10 mg/mL, dissolved in 0.5%methylcellulose, 0.1% Tween® 20), while the other group of rats receivescompound via the intravenous cannula, at a dosing volume of 2 ml/kg (10mg/mL, dissolved in 10% EtOH, 50% PEG 400, 40% saline). The bloodsamples are collected from the arterial cannula at 15, 30, 60, 120, 240,and 360 minutes from the oral group with an additional 3 minute samplebeing collected from IV group. After each sample, the cannulas areflushed with PBS containing 10 units/ml heparin. The animals aresubjected to euthanasia with an excess of anesthesia or carbon monoxideasphyxiation when the study is terminated at 6 hours. Blood samples fromeach time point are assayed for MMP-13 enzyme inhibitory activity andthe circulating concentration of compound plus active metabolites isestimated based on the standard curve.

Pharmacokinetic (PK) parameters are calculated by the VAX computerprogram CSTRIP. The parameters are defined in textbooks such as Goodmanand Gilman's The Pharmacological Basis of Therapeutics, eighth ed.,McGraw-Hill, Inc., New York (1993) and the references therein.

Rat Oral Rat Intraveneous 20 mpk 20 mpk Blood Blood Level AUC Level AUC@ (0-∞) @ (0-6 hr) 6 hr Example t_(½) hr*μg/ 3 min Cmax hr*μg/ BA μg/Number Hour mL μg/mL μg/mL mL % mL 4 1.77 24.80 37.60 1.84 4.14 16.70.254 6 1.19 46.39 84.72 22.88 16.45 35.5 0.345 9 1.10 33.67 42.17 13.639.43 28.0 0.281 10 0.84 43.01 73.00 18.47 12.93 30.1 0.134 12 0.86 22.1173.54 1.00 2.45 11.1 0.121 13 1.03 43.08 91.07 21.98 18.08 42.0 0.228 141.25 12.92 12.10 4.13 7.66 59.3 0.102 15 1.01 49.29 120.83  27.16 18.1936.9 0.192 17 0.74 37.10 63.44 15.72 13.32 35.9 0.135 22 1.47 14.0518.06 0.82 1.82 13.0 0.174 23 0.85 25.01 59.92 7.31 5.93 23.7 0.087 242.49 37.35 62.52 9.79 15.88 42.5 0.545 25 — — — 1.48 0.173 26 0.58 17.5164.01 0.29 0.83 4.7 0.051 27 1.10 43.32 43.69 10.87 21.24 49.0 0.427 28— — — 10.02 24.28 0.537 32 1.03 38.94 51.48 7.65 13.48 34.6 0.529 331.91 29.96 24.13 3.33 8.25 27.5 0.543 34 — — — 2.13 0.495 35 — — — 12.5926.97 1.237 36 0.65  5.74 19.66 0.16 0.73 12.7 0.072 40 — — — 1.55 0.12842 — — — 0.71 0.036 43 0.82 18.79 61.76 4.17 3.24 17.2 0.040 53 0.9710.78 31.68 0.37 0.48 4.4 BLD 65 — — — 0.99 0.080 68 — — — 3.41 0.038 691.87 63.78 44.00 8.58 22.89 35.9 1.172 70 — — — 3.08 0.131 71 — — — 4.000.452 72 — — — 1.42 2.03 0.062 73 — — — 1.89 6.87 0.372 79 1.82  6.1113.99 0.02 0.07 1.1 0.010 80 — — 40.83 0.03 0.003 81 0.76 38.21 89.015.06 6.40 16.7 0.074 89 — — — 1.68 0.196 90 — — — 0.08 0.041 91 — — —0.17 0.138 93 1.81 13.48 20.88 0.35 1.55 11.5 0.126 94 1.71 25.13 43.370.87 1.34 5.3 0.050 95 1.06 19.74 34.71 1.74 4.86 24.6 0.148 96 0.430.076 99 0.68 35.68 99.49 14.25 8.05 22.6 0.071 100 1.50 24.60 26.063.12 11.30 45.9 0.506 103 1.10 19.66 31.11 2.55 0.09 19.9 0.092 104 0.66 9.86 29.82 9.89 4.88 49.4 0.008 108 — — — 2.96 0.108 109 1.12  7.1313.91 0.93 0.85 11.9 0.027 110  2.67 0.02 0.015 111 0.65  8.49 33.560.45 1.11 13.1 0.054 115 1.36  7.81 12.95 1.17 2.00 25.6 0.058 117 0.78 8.69 40.50 0.18 0.28 3.3 0.016 118 1.85 10.97 17.18 0.75 3.32 30.30.268 121 — — — 0.31 0.055 123 — — — 1.43 0.017 125 0.73 15.73 25.361.11 2.50 15.9 0.119 233 0.85 23.12 31.90 3.33 6.22 26.9 0.584 379 1.7451.41 37.54 4.30 16.80 32.7 1.154 382 1.71 73.68 48.81 7.27 36.12 49.03.113 387 — — — 0.65 0.558 388 0.94 26.10 34.62 0.15 0.68 2.6 0.073 3901.50 127.63  120.60  23.21 44.20 34.6 1.780 391 1.45 120.92  82.87 24.0273.24 60.6 2.680 400 104.34  8.55 0.160 408 3.30 25.18 57.40 9.46 4.1716.6 0.015 410 1.78 29.83 40.08 0.63 2.08 6.7 0.223 414 0.73 26.15 61.895.31 6.22 23.8 0.021 416 2.94 230.70  111.17  29.63 156.71 67.9 20.52418 2.42 209.92  78.55 20.65 77.52 36.9 7.347 421 — — — 13.08 19.210.206 427 2.85 36.72 50.74 4.16 8.44 23.0 0.440 437 — — — 4.21 4.430.128 438 2.14  9.05  7.46 0.39 1.86 20.6 0.316

From the foregoing, it will be observed that numerous modifications andvariations can be effectuated without departing from the true spirit andscope of the novel concepts of the present invention. It is to beunderstood that no limitation with respect to the specific examplepresented is intended or should be inferred. The disclosure is intendedto cover by the appended claims all such modifications as fall withinthe scope of the claims.

1. A compound or a pharmaceutically-acceptable salt thereof, wherein:the compound corresponds in structure to formula IV:

R³ is selected from the group consisting of aryl and heteroaryl,wherein: the aryl or heteroaryl is substituted with a substituentselected from the group consisting of cycloalkyl, heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkoxy,heteroarylalkoxy, arylalkoxyalkyl, aryloxyalkyl, arylalkanoylalkyl,arylcarbonylalkyl, arylalkylaryl, aryloxyalkylaryl, arylalkoxyaryl,arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl,alkylthioarylalkyl, arylalkylthioalkyl, arylalkylthioaryl, a sulfoxideof any of the thio substituents, a sulfone of any of the thiosubstituents, and a fused ring structure comprising two or more 5- to6-membered rings selected from the group consisting of aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, wherein: any substitutable substituentof such group optionally is substituted with one or more substituentsindependently selected from the group consisting of cyano,perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl,trifluoromethylalkyl, arylalkoxycarbonyl, aryloxycarbonyl, hydroxy,halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio,arylalkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio,heteroarylalkyl, cycloalkyl, heterocyclooxy, heterocyclothio,heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroarylalkoxy,heteroarylalkylthio, arylalkoxy, arylalkylthio, arylalkylamino,heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy,alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, arylalkanoyl, alkanoyloxy,arylalkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio,alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl,arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl,hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy,alkoxycarbonylalkylthio, amino, carbonylamino, and aminoalkyl, wherein:as to the amino:  the amino nitrogen is optionally substituted with upto two substituents independently selected from the group consisting ofalkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl,alkoxycarbonyl, arylcarbonyl, arylalkanoyl, heteroarylcarbonyl,heteroarylalkanoyl and alkanoyl, or  the amino nitrogen is optionallysubstituted with two substituents such that the amino nitrogen and twosubstituents together form a 5- to 8-membered heterocyclo or heteroarylring that:  optionally contains up to two heteroatoms (in addition tothe amino nitrogen) independently selected from the group consisting ofnitrogen, oxygen, and sulfur, and  optionally is substituted with up totwo substituents independently selected from the group consisting ofaryl, alkyl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy,alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl,trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl,arylalkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofusedheterocycloalkoxy, benzofused cycloalkylcarbonyl,heterocycloalkylcarbonyl, and cycloalkylcarbonyl, as to thecarbonylamino:  the carbonylamino nitrogen is the reacted amine of anamino acid, or  the carbonylamino nitrogen optionally is substitutedwith up to two substituents independently selected from the groupconsisting of alkyl, hydroxyalkyl, hydroxyheteroarylalkyl, cycloalkyl,arylalkyl, trifluoromethylalkyl, heterocycloalkyl, benzofusedheterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl,and N,N-dialkylsubstituted alkylamino-alkyl, or  the carbonylaminonitrogen is optionally substituted with two substituents such that thecarbonylamino nitrogen and two substituents together form a 5- to8-membered heterocyclo, heteroaryl, or benzofused heterocycloalkyl ringthat is optionally substituted with up to two substituents independentlyselected from the group consisting of alkyl, alkoxycarbonyl, nitro,heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, arylalkyl,heteroarylalkyl, and amino, wherein:  the amino nitrogen is optionallysubstituted with up to two substituents independently selected from thegroup consisting of alkyl, aryl, and heteroaryl, or  the amino nitrogenoptionally is substituted with two substituents such that the aminonitrogen and two substituents together form a 5- to 8-memberedheterocyclo or heteroaryl ring, as to the aminoalkyl:  the aminoalkylnitrogen is optionally substituted with up to two substituentsindependently selected from the group consisting of alkyl, aryl,arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and analkanoyl, or  the aminoalkyl nitrogen is optionally substituted with twosubstituents such that the aminoalkyl nitrogen and two substituentstogether form a 5- to 8-membered heterocyclo or heteroaryl ring; and Zis selected from the group consisting of O, S, NR⁶, SO, SO₂, and NSO₂R⁷;and R⁶ is selected from the group consisting of hydrido, C₁-C₅-alkyl,C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl, C₃-C₅-alkenyl,C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl,C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl, C₁-C₅-alkoxyC₁-C₅-alkylcarbonyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkyl,wherein: R⁸ and R⁹ arc independently selected from the group consistingof hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl, andaryl-C₁-C₅-alkoxycarbonyl, or R⁸ and R⁹, together with the nitrogen towhich they are bonded, form a heterocyclic ring containing 5- to 8-atomsin the ring; and R⁷ is selected from the group consisting of arylalkyl,aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl.
 2. A compoundor a pharmaceutically-acceptable salt thereof, wherein: the compoundcorresponds in structure to formula IV:

R³ is selected from the group consisting of phenyl and 5- to 6-memberedheteroaryl, wherein: the phenyl or heteroaryl is substituted at its4-position when a 6-membered ring or at its 3- or 4-position when a5-membered ring with a substituent selected from the group consisting ofphenyl, single-ringed heteroaryl, N-piperidinyl, N-piperazinyl, phenoxy,thiophenoxy, 4-thiopyridyl, phenylazo, and benzamido; and Z is selectedfrom the group consisting of O, S, NR⁶, SO, SO₂, and NSO₂R⁷; and R⁶ isselected from the group consisting of hydrido, C₁-C₅-alkyl,C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl, C₃-C₅-alkenyl,C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl,C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl, C₁-C₅-alkoxyC₁-C₅-alkylcarbonyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkyl,wherein: R⁸ and R⁹ are independently selected from the group consistingof hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl, andaryl-C₁-C₅-alkoxycarbonyl, or R⁸ and R⁹, together with the nitrogen towhich they are bonded, form a heterocyclic ring containing 5- to 8-atomsin the ring; and R⁷ is selected from the group consisting of anarylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl.
 3. A compoundor salt according to claim 2, wherein R³ has a length greater than thelength of a pentyl group and less than the length of an icosyl group. 4.A compound or salt according to claim 2, wherein Z is selected from thegroup consisting of O, S, and NR⁶.
 5. A compound or salt according toclaim 2, wherein R⁶ is selected from the group consisting ofC₃-C₆-cycloalkyl, C₁-C₃-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkyl, C₃-C₅-alkenyl,C₃-C₅-alkynyl, amino-C₁-C₅-alkyl, and heteroaryl-C₁-C₆-alkyl.
 6. Acompound or salt according to claim 2, wherein: R³ is phenyl substitutedat its 4-position by R²³; and R²³ is selected from the group consistingof phenyl, single-ringed heteroaryl, piperidinyl, piperazinyl, phenoxy,thiophenoxy, phenylazo, and benzamido.
 7. A compound or salt accordingto claim 2, wherein the compound corresponds in structure to theformula:


8. A compound or a pharmaceutically-acceptable salt thereof, wherein:the compound corresponds in structure to formula IV:

R³ is phenyl substituted at its 4-position by R²³; and R²³ is selectedfrom the group consisting of phenyl, single-ringed heteroaryl,piperidinyl, piperazinyl, phenoxy, thiophenoxy, phenylazo, andbenzamido, wherein: the phenyl, single-ringed heteroaryl, piperidinyl,piperazinyl, phenoxy, thiophenoxy, phenylazo, or benzamido is:substituted with a substituent selected from the group consisting ofhalogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, dimethylamino, carboxyl C₁-C₃ alkyl,C₁-C₄ alkoxy carbonyl C₁-C₃ alkyl, trifluoromethylthio,trifluoromethoxy, trifluoromethyl, and carboxamido C₁-C₃ alkyl, orsubstituted at the meta- and para-positions by methylenedioxy; and Z isselected from the group consisting of O, S, NR⁶, SO, SO₂, and NSO₂R⁷;and R⁶ is selected from the group consisting of hydrido, C₁-C₅-alkyl,C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl, C₃-C₅-alkenyl,C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl,C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl, C₁-C₅-alkoxyC₁-C₅-alkylcarbonyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkyl,wherein: R⁸ and R⁹ are independently selected from the group consistingof hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl, andaryl-C₁-C₅-alkoxycarbonyl, or R⁸ and R⁹, together with the nitrogen towhich they are bonded, form a heterocyclic ring containing 5- to 8-atomsin the ring; and R⁷ is selected from the group consisting of anarylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl.
 9. A compoundor salt according to claim 8, wherein the R²³ phenyl, single-ringedheteroaryl, piperidinyl, piperazinyl, phenoxy, thiophenoxy, phenylazo,or benzamido is substituted at the para-position.
 10. A compound or saltaccording to claim 9, wherein R²³ is substituted phenoxy.
 11. A compoundor a pharmaceutically-acceptable salt thereof, wherein: the compoundcorresponds in structure to formula IV:

R³ is selected from the group consisting of phenyl and 5- to 6-memberedheteroaryl, wherein: the phenyl or heteroaryl is substituted at its4-position when a 6-membered ring or at its 3- or 4-position when a5-membered ring with a substituent selected from the group consisting ofthiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy,3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy,4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxy-phenoxy,4-trifluoromethylphenoxy, 4-(trifluoronmethylthio)phenoxy,4-(trifluoromethylthio)thiophenoxy, 4-chloro-3-fluorophenoxy,4-isopropoxyphenoxy, 4-isopropylphenoxy,(2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy,4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy,3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy,4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy,3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy,4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy,6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy,5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy,N-piperidinyl, N-piperazinyl, and 4-benzyloxyphenoxy; and Z is selectedfrom the group consisting of O, S, NR⁶, SO, SO₂, and NSO₂R⁷; and R⁶ isselected from the group consisting of hydrido, C₁-C₅-alkyl,C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl, C₃-C₅-alkenyl,C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl,C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl, C₁-C₅-alkoxyC₁-C₅-alkylcarbonyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkyl,wherein: R⁸ and R⁹ are independently selected from the group consistingof hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl, andaryl-C₁-C₅-alkoxycarbonyl, or R⁸ and R⁹, together with the nitrogen towhich they are bonded, form a heterocyclic ring containing 5- to 8-atomsin the ring; and R⁷ is selected from the group consisting of anarylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl.
 12. Acompound or a pharmaceutically acceptable salt thereof, wherein: thecompound corresponds in structure to formula IV:

R³ is G—A—R—E—Y; and G—A—R—E—Y comprises at least two ring structures;and G is selected from the group consisting of aryl and heteroaryl; andA is selected from the group consisting of: (1) —O—, (2) —S—, (3) —NR¹⁷,(4) —CO—N(R¹⁷)—, (5) —N(R¹⁷)—CO—, (6) —CO—O—, (7) —O—CO—, (8) —O—CO—O—,(9) —HC═CH—, (10) —NH—CO—NH—, (11) —C≡C—, (12) —NH—CO—O—, (13)—O—CO—NH—, (14) —N═N—, (15) —NH—NH—, (16) —CS—N(R¹⁸)—, (17) —N(R¹⁸)—CS—,and (18) a bond; and R¹⁷ is selected from the group consisting ofhydrido, C₁-C₄ alkyl, and phenyl; and R¹⁸ is selected from the groupconsisting of hydrido, C₁-C₄ alkyl, and phenyl; and R is selected fromthe group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl,heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl,heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl,wherein: the aryl, heteroaryl, cycloalkyl, or heterocycloalkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of halo, alkyl, perfluoroalkyl,perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino,alkoxycarbonylalkyl, alkoxy, C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl,hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino,and alkoxycarbonyl; and R is other than alkyl or alkoxyalkyl when A is—O— or —S—; and E is selected from the group consisting of: (1)—CO(R¹⁹)—, (2) —(R¹⁹)CO—, (3) —CONH—, (4) —HNCO—, (5) —CO—, (6)—SO₂—R¹⁹—, (7) —R¹⁹—SO₂—, (8) —SO₂—, (9) —NH—SO₂—, (10) —SO₂—NH—, and(11) a bond; and R¹⁹ is selected from the group consisting ofheterocycloalkyl and cycloalkyl; and Y is selected from the groupconsisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, arylalkyl,cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio,trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl,trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl,heteroaryl, or heterocycloalkyl optionally is substituted with up to twosubstituents independently selected from the group consisting ofalkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, and amino, wherein: theamino nitrogen optionally is substituted with up to two substituentsindependently selected from the group consisting of alkyl and arylalkyl;and Z is selected from the group consisting of O, S, NR⁶, SO, SO₂, andNSO₂R⁷; and R⁶ is selected from the group consisting of hydrido,C₁-C₅-alkyl, C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl,C₃-C₅-alkenyl, C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl,heteroaryl-C₁-C₆-alkyl, C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl,C₁-C₅-alkoxy C₁-C₅-alkylcarbonyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, andNR⁸R⁹—C₁-C₅-alkyl, wherein: R⁸ and R⁹ are independently selected fromthe group consisting of hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl, andaryl-C₁-C₅-alkoxycarbonyl, or R⁸ and R⁹, together with the nitrogen towhich they are bonded, form a heterocyclic ring containing 5- to 8-atomsin the ring; and R⁷ is selected from the group consisting of arylalkyl,aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl,C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl.
 13. Acompound or salt according to claim 12, wherein —G—A—R—E—Y contains twoto four carbocyclic or heterocyclic rings.
 14. A compound or saltaccording to claim 13, wherein each of the two to four rings is6-membered.
 15. A compound or salt according to claim 12, wherein—G—A—R—E—Y has a length greater than the length of a hexyl group andless than the length of a stearyl group.
 16. A compound or saltaccording to claim 12, wherein A is selected from the group consistingof —O— and —S—.
 17. A compound or salt according to claim 12, wherein Ris selected from the group consisting of aryl, heteroaryl, cycloalkyl,and heterocycloalkyl.
 18. A compound or salt according to claim 12,wherein E is a bond.
 19. A compound or salt according to claim 12,wherein Y is selected from the group consisting of hydrido, alkyl,alkoxy, perfluoroalkoxy, and perfluoroalkylthio.
 20. A method fortreating a mammal having a condition associated with pathological matrixmetalloprotease (MMP) activity, wherein: the process comprisesadministering a therapeutically-effective amount of a compound or saltrecited in claim 1 to the mammal; and the compound or salt inhibits theactivity of MMP-2, MMP-9, and/or MMP-13, while exhibiting substantiallyless inhibiting activity against MMP-1.
 21. A method for treating amammal having a condition associated with pathological matrixmetalloprotease (MMP) activity, wherein: the process comprisesadministering a therapeutically-effective amount of a compound or saltrecited in claim 2 to the mammal; and the compound or salt inhibits theactivity of MMP-2, MMP-9, and/or MMP-13, while exhibiting substantiallyless inhibiting activity against MMP-1.
 22. A method according to claim21, wherein R³ has a length greater than the length of a pentyl groupand less than the length of an icosyl group.
 23. A method according toclaim 21, wherein Z is selected from the group consisting of O, S, andNR⁶.
 24. A method for treating a mammal having a condition associatedwith pathological matrix metalloprotease (MMP) activity, wherein: theprocess comprises administering a therapeutically-effective amount of acompound or salt recited in claim 8 to the mammal; and the compound orsalt inhibits the activity of MMP-2, MMP-9, and/or MMP-13, whileexhibiting substantially less inhibiting activity against MMP-1.
 25. Amethod for treating a mammal having a condition associated withpathological matrix metalloprotease (MMP) activity, wherein: the processcomprises administering a therapeutically-effective amount of a compoundor salt recited in claim 11 to the mammal; and the compound or saltinhibits the activity of MMP-2, MMP-9, and/or MMP-13, while exhibitingsubstantially less inhibiting activity against MMP-1.
 26. A methodaccording to claim 25, wherein the compound corresponds in structure tothe formula:


27. A method for treating a mammal having a condition associated withpathological matrix metalloprotease (MMP) activity, wherein: the processcomprises administering a therapeutically-effective amount of a compoundor salt recited in claim 12 to tie mammal; and the compound or saltinhibits the activity of MMP-2, MMP-9, and/or MMP-13, while exhibitingsubstantially less inhibiting activity against MMP-1.
 28. A methodaccording to claim 27 wherein —G—A—R—E—Y contains two to fourcarbocyclic or heterocyclic rings.
 29. A method according to claim 28,wherein each of the two to four rings is 6-membered.
 30. A methodaccording to claim 27, wherein —G—A—R—E—Y has a length that is greaterthan the length of an octyl group and less than the length of a stearylgroup.
 31. A method according to claim 27, wherein A is selected fromthe group consisting of —O— and —S—.
 32. A method according to claim 27,wherein R is selected from the group consisting of aryl, heteroaryl,cycloalkyl, and heterocycloalkyl.
 33. A method according to claim 27,wherein E is a bond.
 34. A method according to claim 27, wherein Y isselected from the group consisting of hydrido, alkyl, alkoxy,perfluoroalkoxy, and perfluoroalkylthio.
 35. A pharmaceuticalcomposition, wherein the composition comprises atherapeutically-effective amount of a compound or salt recited in claim1 dissolved or dispersed in a pharmaceutically-acceptable carrier.
 36. Apharmaceutical composition, wherein the composition comprises atherapeutically-effective amount of a compound or salt recited in claim2 dissolved or dispersed in a pharmaceutically-acceptable carrier.
 37. Apharmaceutical composition, wherein the composition comprises atherapeutically-effective amount of a compound or salt recited in claim8 dissolved or dispersed in a pharmaceutically-acceptable carrier.
 38. Apharmaceutical composition, wherein the composition comprises atherapeutically-effective amount of a compound or salt recited in claim11 dissolved or dispersed in a pharmaceutically-acceptable carrier. 39.A pharmaceutical composition, wherein the composition comprises atherapeutically-effective amount of a compound or salt recited in claim12 dissolved or dispersed in a pharmaceutically-acceptable carrier.